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1
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Bolek H, Yazgan SC, Yekedüz E, Kaymakcalan MD, McKay RR, Gillessen S, Ürün Y. Androgen receptor pathway inhibitors and drug-drug interactions in prostate cancer. ESMO Open 2024; 9:103736. [PMID: 39426080 PMCID: PMC11533040 DOI: 10.1016/j.esmoop.2024.103736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/22/2024] [Accepted: 08/30/2024] [Indexed: 10/21/2024] Open
Abstract
Prostate cancer represents a major global health challenge, necessitating efficacious therapeutic strategies. Androgen receptor pathway inhibitors (ARPIs) have become central to prostate cancer treatment, demonstrating significant effectiveness in both metastatic and non-metastatic contexts. Abiraterone acetate, by inhibiting androgen synthesis, deprives cancer cells androgens necessary for growth, while second-generation androgen receptor (AR) antagonists disrupt AR signaling by blocking AR binding, thereby impeding tumor progression. Given the predominance of prostate cancer in the elderly, who often present with multiple comorbidities requiring complex pharmacological regimens, the potential for drug-drug interactions with ARPIs is a critical concern. These interactions, particularly through pathways like CYP2D6 inhibition by abiraterone and CYP3A4 induction by enzalutamide and apalutamide, necessitate a thorough understanding to optimize therapeutic outcomes and minimize adverse effects. This review aims to delineate the efficacy of ARPIs in prostate cancer management and elucidate their interaction with common medications, highlighting the importance of vigilant drug management to optimize patient care.
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Affiliation(s)
- H Bolek
- Department of Medical Oncology, Ankara University School of Medicine, Ankara; Ankara University Cancer Research Institute, Ankara, Turkey
| | - S C Yazgan
- Department of Medical Oncology, Ankara University School of Medicine, Ankara; Ankara University Cancer Research Institute, Ankara, Turkey
| | - E Yekedüz
- Dana-Farber Cancer Institute, Harvard Medical School, Boston
| | | | - R R McKay
- Moores Cancer Center, University of California San Diego, La Jolla, USA
| | - S Gillessen
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona; Faculty of Biomedical Sciences, USI, Lugano, Switzerland
| | - Y Ürün
- Department of Medical Oncology, Ankara University School of Medicine, Ankara; Ankara University Cancer Research Institute, Ankara, Turkey.
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Al-Bari MAA, Peake N, Eid N. Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges. World J Diabetes 2024; 15:853-866. [PMID: 38766427 PMCID: PMC11099355 DOI: 10.4239/wjd.v15.i5.853] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/08/2024] [Accepted: 03/21/2024] [Indexed: 05/10/2024] Open
Abstract
Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.
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Affiliation(s)
| | - Nicholas Peake
- Biosciences and Chemistry and Biomolecular Research Centre, Sheffield Hallam University, Sheffield S1 1WB, United Kingdom
| | - Nabil Eid
- Department of Anatomy, Division of Human Biology, School of Medicine, International Medical University, Kuala Lumpur 57000, Malaysia
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3
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Adiwidjaja J, Sasongko L. Effect of Nigella sativa oil on pharmacokinetics and pharmacodynamics of gliclazide in rats. Biopharm Drug Dispos 2021; 42:359-371. [PMID: 34327715 DOI: 10.1002/bdd.2300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/22/2021] [Accepted: 07/26/2021] [Indexed: 11/11/2022]
Abstract
Nigella sativa oil (NSO) has been used widely for its putative anti-hyperglycemic activity. However, little is known about its potential effect on the pharmacokinetics and pharmacodynamics of antidiabetic drugs, including gliclazide. This study aimed to investigate herb-drug interactions between gliclazide and NSO in rats. Plasma concentrations of gliclazide (single oral and intravenous dose of 33 and 26.4 mg/kg, respectively) in the presence and absence of co-administration with NSO (52 mg/kg per oral) were quantified in healthy and insulin resistant rats (n = 5 for each group). Physiological and treatment-related factors were evaluated as potential influential covariates using a population pharmacokinetic modeling approach (NONMEM version 7.4). Clearance, volume of distribution and bioavailability of gliclazide were unaffected by disease state (healthy or insulin resistant). The concomitant administration of NSO resulted in higher systemic exposures of gliclazide by modulating bioavailability (29% increase) and clearance (20% decrease) of the drug. A model-independent analysis highlighted that pre-treatment with NSO in healthy rats was associated with a higher glucose lowering effect by up to 50% compared with that of gliclazide monotherapy, but not of insulin resistant rats. Although a similar trend in glucose reductions was not observed in insulin resistant rats, co-administration of NSO improved the sensitivity to insulin of this rat population. Natural product-drug interaction between gliclazide and NSO merits further evaluation of its clinical importance.
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Affiliation(s)
- Jeffry Adiwidjaja
- School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia.,Sydney Pharmacy School, The University of Sydney, Sydney, Australia
| | - Lucy Sasongko
- School of Pharmacy, Institut Teknologi Bandung, Bandung, Indonesia
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Lai JH, Wang MT, Wu CC, Huang YL, Lu CH, Liou JT. Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study. Pharmacoepidemiol Drug Saf 2020; 29:842-853. [PMID: 32483856 DOI: 10.1002/pds.5034] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/03/2020] [Accepted: 05/05/2020] [Indexed: 01/16/2023]
Abstract
PURPOSE To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. METHODS We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). RESULTS We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). CONCLUSIONS Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.
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Affiliation(s)
- Jyun-Heng Lai
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Meng-Ting Wang
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Chao Wu
- Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Ya-Ling Huang
- School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Chieh-Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jun-Ting Liou
- Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
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Shaik M, Shaik S, Kilari EK. Population pharmacokinetics of gliclazide in normal and diabetic rabbits. Biopharm Drug Dispos 2018; 39:265-274. [PMID: 29679474 DOI: 10.1002/bdd.2132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/29/2018] [Accepted: 04/15/2018] [Indexed: 12/20/2022]
Abstract
Gliclazide is a second-generation sulphonylurea drug widely used in the treatment of type 2 diabetes. However, there is no single report to describe the population pharmacokinetics of gliclazide in animal models. This study was aimed to evaluate the population pharmacokinetics (PK) of gliclazide in normal and alloxan-induced diabetic rabbits using nonlinear mixed effects modeling. A total of 90 New Zealand white rabbits were administered with three doses (4.13, 8.27 and 16.53 mg/kg b.wt) of gliclazide by an oral route. Blood samples were collected up to 24 hr and the gliclazide concentrations in rabbit were determined using the HPLC method. The non-compartmental and classical compartmental PK analyses were performed using Phoenix WinNonlin. Population PK analysis of gliclazide was performed using nonlinear mixed-effects model software NONMEM and Phoenix NLME considering the weight, age, sex, health and dose as covariates. The final population values for clearance (CL), volume of distribution (V) and the absorption rate constant (ka ) were 5270 ml/hr, 55700 ml and 0.708 hr-1 , respectively. The inter-individual variability in gliclazide CL, V and ka was 16.3%, 14.9% and 26.5%, respectively. There was no significant difference between NONMEM and Phoenix NLME pharmacokinetic results. The visual predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates from this model. This population PK model demonstrated that gliclazide pharmacokinetics is best described by one-compartment model with first-order absorption in rabbits. Body weight is a covariate that significantly influences gliclazide kinetic disposition in rabbits.
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Affiliation(s)
- Mastan Shaik
- Troikaa Pharmaceuticals Ltd, Medical Services, Satyamarg, Bodakdev, Ahmedabad Gujarat, India
| | - Shabana Shaik
- Research Consultant, Venkata Reddy Nagar, Nellore, Andhra Pradesh, India
| | - Eswar Kumar Kilari
- Andhra University College of Pharmaceutical Sciences, Pharmacology Division, Visakhapatnam, Andhra Pradesh, India
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Jhaj R, Sharma S, Sabir M, Kokane A. A pilot study to determine the occurrence of concomitant diseases and drug intake in patients on antituberculosis therapy. J Family Med Prim Care 2018; 7:414-419. [PMID: 30090786 PMCID: PMC6060940 DOI: 10.4103/jfmpc.jfmpc_103_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Introduction: Altered pharmacokinetics of antituberculosis (anti-TB) drugs due to interaction with non-TB medications or concomitant diseases may lead to suboptimal plasma levels of the affected drugs and hence contribute to the emergence of drug resistance in mycobacteria. Yet, few studies have investigated the prevalence of concomitant drug intake or concurrent diseases in patients on anti-TB therapy (ATT). The objective of this study is to study the prevalence of concomitant diseases and intake of non-TB drugs in patients on ATT. Methods: Adult patients who were undergoing treatment for TB at a directly observed treatment short-course (DOTS) center were interviewed to find out any concomitant drug intake and ailments they were suffering from. Data were also collected from the patients’ treatment cards. Results: A total of 105 patients were interviewed for the study over a period of 1 month. Among these, 66 (62.9%) patients reported having taken a non-ATT drug in the last 3 months, 61 (58.1%) of which were drugs that may affect the ATT. A comparable number of patients (61 [58.1%]) reported suffering from one or the other concurrent illnesses or symptoms while on DOTS, including one patient with AIDS and eight with diabetes mellitus. Fluoroquinolones had been prescribed to four patients while on DOTS. Conclusion: A large proportion of the patients with TB were found to be on non-TB concomitant medications including drugs with potential for interactions that are capable of affecting ATT outcomes. It is, therefore, important that the patients and prescribing physicians be aware of any possible drug interactions.
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Affiliation(s)
- Ratinder Jhaj
- Department of Pharmacology and Toxicology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Shweta Sharma
- Department of Pharmacology and Toxicology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Mohammed Sabir
- Department of Medical Student, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Arun Kokane
- Department of Community and Family Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
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Proks P, Kramer H, Haythorne E, Ashcroft FM. Binding of sulphonylureas to plasma proteins - A KATP channel perspective. PLoS One 2018; 13:e0197634. [PMID: 29772022 PMCID: PMC5957440 DOI: 10.1371/journal.pone.0197634] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 05/04/2018] [Indexed: 12/25/2022] Open
Abstract
Sulphonylurea drugs stimulate insulin secretion from pancreatic β-cells primarily by inhibiting ATP sensitive potassium (KATP) channels in the β-cell membrane. The effective sulphonylurea concentration at its site of action is significantly attenuated by binding to serum albumin, which makes it difficult to compare in vitro and in vivo data. We therefore measured the ability of gliclazide and glibenclamide to inhibit KATP channels and stimulate insulin secretion in the presence of serum albumin. We used this data, together with estimates of free drug concentrations from binding studies, to predict the extent of sulphonylurea inhibition of KATP channels at therapeutic concentrations in vivo. KATP currents from mouse pancreatic β-cells and Xenopus oocytes were measured using the patch-clamp technique. Gliclazide and glibenclamide binding to human plasma were determined in spiked plasma samples using an ultrafiltration-mass spectrometry approach. Bovine serum albumin (60g/l) produced a mild, non-significant reduction of gliclazide block of KATP currents in pancreatic β-cells and Xenopus oocytes. In contrast, glibenclamide inhibition of recombinant KATP channels was dramatically suppressed by albumin (predicted free drug concentration <0.1%). Insulin secretion was also reduced. Free concentrations of gliclazide and glibenclamide in the presence of human plasma measured in binding experiments were 15% and 0.05%, respectively. Our data suggest the free concentration of glibenclamide in plasma is too low to account for the drug’s therapeutic effect. In contrast, the free gliclazide concentration in plasma is high enough to close KATP channels and stimulate insulin secretion.
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Affiliation(s)
- Peter Proks
- Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Holger Kramer
- Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Elizabeth Haythorne
- Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Frances M. Ashcroft
- Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
- * E-mail:
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Anusha A, Narendar D, Krishna Murthy B, Goverdhan P. Influence of Single and Multi Dose Treatment of Glipizide on Pharmacokinetics and Pharmacodynamics of Irbesartan in Normal and Hypertensive Rats. High Blood Press Cardiovasc Prev 2017; 24:179-185. [DOI: 10.1007/s40292-017-0195-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/20/2017] [Indexed: 11/28/2022] Open
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Habtewold A, Aklillu E, Makonnen E, Amogne W, Yimer G, Aderaye G, Bertilsson L, Owen JS, Burhenne J. Long-Term Effect of Rifampicin-Based Anti-TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8-Hydroxy-Efavirenz in Ethiopian Patients. J Clin Pharmacol 2016; 56:1538-1549. [PMID: 27125860 DOI: 10.1002/jcph.756] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 04/20/2016] [Accepted: 04/21/2016] [Indexed: 12/29/2022]
Abstract
We compared the pharmacokinetic (PK) exposure parameters of efavirenz (EFV) and its major inactive metabolite, 8-hydroxy-efavirenz (8-OH-EFV), in an open-label, single-sequence, and parallel design of HIV-infected and tuberculosis (TB)-HIV-coinfected Ethiopian patients in the HIV-TB Pharmagene study with 20 and 33 patients, respectively. Both treatment groups underwent PK sampling following oral 600 mg EFV in week 16 of initiating EFV-based combination antiretroviral therapy. The TB-HIV-coinfected group repeated the PK sampling 8 weeks after stopping rifampin (RIF)-based anti-TB treatment. Between-treatment group analysis indicated no significant effect of RIF-based anti-TB cotreatment on PK exposure parameters of EFV, nor was there a significant effect after controlling for sex or CYP2B6 genotype. However, RIF-based therapy in TB-HIV-coinfected patients had significantly increased 8-OH-EFV PK exposure measures and metabolic ratio relative to HIV-only patients, AUC0-24 greater by 79%. The effect was more prominent in women and CYP2B6*6 carriers in within-sex and CYP2B6 genotype comparisons. Within-subject comparisons for AUC0-24 and Cmax when "on" and "off" RIF-based anti-TB cotreatment showed geometric mean ratios (90% confidence intervals) of 100.5% (98.7%-102.3%) and 100.2% (98.1%-102.4%), respectively, for EFV and 98.6% (95.5%-101.7%-) and 97.6% (92.2%-103.0%), respectively, for 8-OH-EFV. We report no significant influence of RIF-based anti-TB cotherapy on the EFV PK exposure measures. The study also calls for caution related to higher exposure to 8-OH-EFV during simultaneous coadministration of EFV and RIF-based anti-TB regimens, which may be associated with neurotoxicity, particularly in female patients and CYP2B6*6 carriers.
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Affiliation(s)
- Abiy Habtewold
- Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson, TN, USA.,Division of Clinical Pharmacology, Department of Lab Medicine, Karolinska Institutet Hospital Huddinge, Stockholm, Sweden.,Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Eleni Aklillu
- Section of Pharmacogenetics, Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Eyasu Makonnen
- Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Wondwossen Amogne
- Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Getnet Yimer
- Department of Pharmacology, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Getachew Aderaye
- Department of Internal Medicine, School of Medicine, Addis Ababa University, Addis Ababa, Ethiopia
| | - Leif Bertilsson
- Division of Clinical Pharmacology, Department of Lab Medicine, Karolinska Institutet Hospital Huddinge, Stockholm, Sweden
| | - Joel S Owen
- Department of Pharmaceutical Sciences, School of Pharmacy, Union University, Jackson, TN, USA
| | - Jürgen Burhenne
- Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital of Heidelberg, Heidelberg, Germany
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Ahad A, Al-Saleh AA, Akhtar N, Al-Mohizea AM, Al-Jenoobi FI. Transdermal delivery of antidiabetic drugs: formulation and delivery strategies. Drug Discov Today 2015; 20:1217-27. [DOI: 10.1016/j.drudis.2015.06.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 05/17/2015] [Accepted: 06/10/2015] [Indexed: 10/23/2022]
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Zhao RY, He XW, Shan YM, Zhu LL, Zhou Q. A stewardship intervention program for safe medication management and use of antidiabetic drugs. Clin Interv Aging 2015; 10:1201-12. [PMID: 26229454 PMCID: PMC4516029 DOI: 10.2147/cia.s87456] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Background Diabetes patients are complex due to considerations of polypharmacy, multimorbidities, medication adherence, dietary habits, health literacy, socioeconomic status, and cultural factors. Meanwhile, insulin and oral hypoglycemic agents are high-alert medications. Therefore it is necessary to require a multidisciplinary team’s integrated endeavors to enhance safe medication management and use of antidiabetic drugs. Methods A 5-year stewardship intervention program, including organizational measures and quality improvement activities in storage, prescription, dispensing, administration, and monitoring, was performed in the Second Affiliated Hospital of Zhejiang University, People’s Republic of China, a 3,200-bed hospital with 3.5 million outpatient visits annually. Results The Second Affiliated Hospital of Zhejiang University has obtained a 100% implementation rate of standard storage of antidiabetic drugs in the Pharmacy and wards since August 2012. A zero occurrence of dispensing errors related to highly “look-alike” and “sound-alike” NovoMix 30® (biphasic insulin aspart) and NovoRapid® (insulin aspart) has been achieved since October 2011. Insulin injection accuracy among ward nurses significantly increased from 82% (first quarter 2011) to 96% (fourth quarter 2011) (P<0.05). The number of medication administration errors related to insulin continuously decreased from 20 (2011) to six (2014). The occurrence rate of hypoglycemia in non–endocrinology ward diabetes inpatients during 2011–2013 was significantly less than that in 2010 (5.03%–5.53% versus 8.27%) (P<0.01). Percentage of correct management of hypoglycemia by nurses increased from 41.5% (April 2014) to 67.2% (August 2014) (P<0.01). The percentage of outpatient diabetes patients receiving standard insulin injection education increased from 80% (April 2012) to 95.2% (October 2012) (P<0.05). Insulin injection techniques among diabetes outpatients who started to receive insulin were better than indicated in data from two questionnaire surveys in the literature, including the percentage checking injection sites prior to injection (85.6%), priming before injection (98.1%), rotation of injecting sites (98.1%), remixing before use (94.5%), keeping the pen needle under the skin for >10 seconds (99.4%), and using the pen needle only once (88.7%). On-site inspection indicated of great improvement in the percentage of drug-related problems in the antidiabetes regimen between the first and second quarter of 2014 (1.08% versus 0.28%) (P<0.05). Conclusion Quality improvements in safe medication management and use of antidiabetic drugs can be achieved by multidisciplinary collaboration among pharmacists, nurses, physicians, and information engineers.
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Affiliation(s)
- Rui-yi Zhao
- Clinical Nurse Specialist Section, Division of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Xiao-wen He
- Clinical Nurse Specialist Section, Division of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yan-min Shan
- Clinical Nurse Specialist Section, Division of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Ling-ling Zhu
- Geriatric VIP Care Ward, Division of Nursing, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
| | - Quan Zhou
- Department of Pharmacy, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China
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Pérez-Navarro LM, Fuentes-Domínguez FJ, Zenteno-Cuevas R. Type 2 diabetes mellitus and its influence in the development of multidrug resistance tuberculosis in patients from southeastern Mexico. J Diabetes Complications 2015; 29:77-82. [PMID: 25303784 DOI: 10.1016/j.jdiacomp.2014.09.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 08/19/2014] [Accepted: 09/10/2014] [Indexed: 11/26/2022]
Abstract
AIMS To determine the factors associated with the presence of pulmonary tuberculosis in patients with type 2 diabetes mellitus and the effect in the development of drug and multi-drug resistance, in a population with tuberculosis from the southeast of Mexico. METHODS This is a case-control study including 409 individuals, 146 with the binomial tuberculosis-type 2 diabetes mellitus and 263 individuals with tuberculosis. Demographic, epidemiological and outcome variables were collected. Risks were calculated. RESULTS The factors associated with the presence of type 2 diabetes mellitus were age ≥35years, (OR=9.7; CI: 5.2-17.8), previous contact with a person infected with tuberculosis (OR=1.7; CI: 1.1-3.1). Body mass index ≥25 kg/m(2) (OR=2.2; CI: 1.1-4.3), and inherited family history of diabetes (OR=5.4; CI: 3.2-9.2). It was also found that patients with tuberculosis-type 2 diabetes mellitus presented a 4.7-fold (CI: 1.4-11.3) and 3.5-fold (CI: 1.1-11.1) higher risk of developing drug- and multidrug resistance tuberculosis, respectively. By last, individuals with tuberculosis-type 2 diabetes had a 2.3-fold (CI: 1.5-4.1) greater chance of persisting as tuberculosis-positive by the second month of treatment, delaying the resolution of the tuberculosis infection. CONCLUSIONS Type 2 diabetes exerts a strong influence on the presentation and evolution of tuberculosis within the analyzed population and displays remarkable particularities, necessitating the development of dedicated tuberculosis-diabetes surveillance systems that consider the particular epidemiological characteristics of the population affected.
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Affiliation(s)
- Lucia Monserrat Pérez-Navarro
- Public Health Institute, University of Veracruz, Veracruz, Mexico; Doctoral program in Biomedical Sciences, Biomedical Research Center, University of Veracruz, Veracruz, México.
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Abstract
A broad spectrum of endocrine conditions has been reported among adult patients with tuberculosis in Africa. This review aims to describe the magnitude and pathogenesis of the following endocrinopathies among patients with tuberculosis in Africa: adrenal insufficiency, diabetes mellitus, disorders of calcium and vitamin D metabolism, thyroid dysfunction and hypogonadism. PubMed database and Google scholar were used to search for the relevant published English language studies and case reports relating to endocrine abnormalities and tuberculosis in Africa up to July 2013. The search terms used were endocrine dysfunction, endocrine abnormalities, adrenal insufficiency, diabetes mellitus, thyroid dysfunction, hypogonadism, disorders of calcium and vitamin D metabolism, tuberculosis, Africa. Reference lists of the identified articles were further used to identify other studies. Adrenal insufficiency, diabetes mellitus and calcium-vitamin D abnormalities were the most prevalent and frequently reported endocrine disorders among adult patients with tuberculosis in Africa. A meticulous endocrine evaluation among tuberculosis patients with suspected endocrine abnormalities should be encouraged in Africa and other high TB endemic regions. Treatment of these endocrine disorders has generally been shown to improve quality of life and reduce mortality.
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Affiliation(s)
- Davis Kibirige
- Department of Medicine, Uganda Martyrs Hospital Lubaga, Kampala, Uganda
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Gotoh S, Negishi M. Serum- and glucocorticoid-regulated kinase 2 determines drug-activated pregnane X receptor to induce gluconeogenesis in human liver cells. J Pharmacol Exp Ther 2014; 348:131-40. [PMID: 24204015 PMCID: PMC3868883 DOI: 10.1124/jpet.113.209379] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Accepted: 11/05/2013] [Indexed: 11/22/2022] Open
Abstract
Drug activation of the human nuclear pregnane X receptor (PXR) induced gluconeogenic genes and increased glucose production. In this study, we have determined that serum- and glucocorticoid-regulated kinase 2 (SGK2) is an essential factor that mediates this PXR-regulated glucose 6-phosphatase (G6Pase) induction and glucose production. Both SGK2 and G6Pase mRNAs were increased in rifampicin-treated HepG2 cells stably expressing human PXR. Reporter and chromatin immunoprecipitation assays delineated PXR activation of the SGK2 gene to a distal and proximal DNA sequence within its promoter: distal PXR response element (-2587/-2209) and proximal PXR response element (-115/-75), respectively. Small interfering RNA (siRNA) knockdown of SGK2 severely attenuated PXR-regulated induction of G6Pase as well as glucose production. SGK2 constitutes an insulin-independent signal pathway to regulate gluconeogenesis because siRNA knockdown of the insulin-responsive transcription factor forkhead box protein O1 did not affect rifampicin induction of G6Pase. Rifampicin treatment of two different samples of human primary hepatocytes revealed that PXR induces G6Pase in the presence of high levels of SGK2, whereas PXR represses G6Pase in its absence. Mediating PXR activation of the G6Pase gene is the first biological role found for hepatic SGK2 and might have therapeutic implications for side effects, such as diabetes, caused by drugs that activate PXR.
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Affiliation(s)
- Saki Gotoh
- Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
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15
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Cieniak C, Liu R, Fottinger A, Smiley SAM, Guerrero-Analco JA, Bennett SAL, Haddad PS, Cuerrier A, Saleem A, Arnason JT, Foster BC. In vitro inhibition of metabolism but not transport of gliclazide and repaglinide by Cree medicinal plant extracts. JOURNAL OF ETHNOPHARMACOLOGY 2013; 150:1087-1095. [PMID: 24184081 DOI: 10.1016/j.jep.2013.10.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 10/10/2013] [Accepted: 10/13/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Interactions between conventional drug and traditional medicine therapies may potentially affect drug efficacy and increase the potential for adverse reactions. Cree traditional healing is holistic and patients may use medicinal plants simultaneously with the conventional drugs. However, there is limited information that these medicinal plants may interact with drugs and additional mechanistic information is required. In this study, extracts from traditionally used Cree botanicals were assessed for their potential interaction that could alter the disposition of two blood glucose lowering drugs, gliclazide (Diamicron) and repaglinide (Gluconorm) though inhibition of either metabolism or transport across cell membranes. MATERIALS AND METHODS The effect of 17 extracts on metabolism was examined in a human liver microsome assay by HPLC and individual cytochrome P450s 2C9, 2C19, 2C8 and 3A4 in a microplate fluorometric assay. Gliclazide, rhaponticin and its aglycone derivative, rhapontigenin were also examined in the fluorometric assay. The effect on transport was examined with 11 extracts using the intestinal epithelial Caco-2 differentiated cell monolayer model at times up to 180 min. RESULTS Both blood glucose lowering medications, gliclazide and repaglinide traversed the Caco-2 monolayer in a time-dependent manner that was not affected by the Cree plant extracts. Incubation of the Cree plant extracts inhibited CYP2C9, 2C19, 2C8 and 3A4-mediated metabolism, and the formation of four repaglinide metabolites: M4, m/z 451-A, m/z 451-B and the glucuronide of repaglinide in the human liver microsome assay. Gliclazide caused no significant inhibition. Likewise, rhaponticin had little effect on the enzymes causing changes of less than 10% with an exception of 17% inhibition of CYP2C19. By contrast, the aglycone rhapontigenin showed the greatest effects on all CYP-mediated metabolism. Its inhibition ranged from a mean of 58% CYP3A4 inhibition to 89% inhibition of CYP2C9. While rhaponticin and the aglycone did not show significant effects on repaglinide metabolism, they demonstrated inhibition of gliclazide metabolism. The aglycone significantly affected levels of gliclazide and its metabolites. CONCLUSION These studies demonstrate that the Cree plant extracts examined have the potential in vitro to cause drug interactions through effects on key metabolic enzymes.
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Affiliation(s)
- Carolina Cieniak
- Biology Department, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
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16
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Tuberculosis and Diabetes Mellitus Interaction. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2013. [DOI: 10.1097/ipc.0b013e31828f4b53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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17
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Tod M, Nkoud-Mongo C, Gueyffier F. Impact of genetic polymorphism on drug-drug interactions mediated by cytochromes: a general approach. AAPS JOURNAL 2013; 15:1242-52. [PMID: 24027036 DOI: 10.1208/s12248-013-9530-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/06/2013] [Accepted: 08/19/2013] [Indexed: 11/30/2022]
Abstract
Currently, quantitative prediction of the impact of genetic polymorphism and drug-drug interactions mediated by cytochromes, based on in vivo data, is made by two separate methods and restricted to a single cytochrome. We propose a unified approach for describing the combined impact of drug-drug interactions and genetic polymorphism on drug exposure. It relies on in vivo data and uses the following three characteristic parameters: one for the victim drug, one for the interacting drug, and another for the genotype. These parameters are known for a wide range of drugs and genotypes. The metrics of interest are the ratio of victim drug area under the curve (AUC) in patients with genetic variants taking both drugs, to the AUC in patients with either variant or wild-type genotype taking the victim drug alone. The approach was evaluated by external validation, comparing predicted and observed AUC ratios found in the literature. Data were found for 22 substrates, 30 interacting drugs, and 38 substrate-interacting drug couples. The mean prediction error of AUC ratios was 0.02, and the mean prediction absolute error was 0.38 and 1.34, respectively. The model may be used to predict the variations in exposure resulting from a number of drug-drug-genotype combinations. The proposed approach will help (1) to identify comedications and population at risk, (2) to adapt dosing regimens, and (3) to prioritize the clinical pharmacokinetic studies to be done.
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Affiliation(s)
- Michel Tod
- Hospices Civils de Lyon, Université de Lyon, Université Lyon 1, 69000, Lyon, France,
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18
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Kapur A, Harries AD. The double burden of diabetes and tuberculosis - public health implications. Diabetes Res Clin Pract 2013; 101:10-9. [PMID: 23305899 DOI: 10.1016/j.diabres.2012.12.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 12/10/2012] [Indexed: 01/04/2023]
Abstract
Diabetes mellitus (DM) and tuberculosis (TB) have existed for thousands of years and even now the global disease burden from DM and TB is huge. The incidence of TB is declining slowly but it still remains a big problem in many populous large low and middle income countries. On the other, hand the burden of diabetes is increasing very rapidly, particularly in the very same countries where TB is endemic. The intersecting double burden is therefore ominous particularly as several studies and systematic reviews have indicated that DM increases the risk of TB disease and results in poor treatment outcomes. To address the double burden, WHO and the International Union Against Tuberculosis and Lung Disease (The Union) in 2011 launched a collaborative framework for the care and control of diabetes and tuberculosis, to encourage collaborative research and implement bidirectional screening of the two diseases in routine settings. This review article (i) explores some of the new evidence for the association between TB and DM, (ii) discusses issues with regard to clinical presentation and outcomes, (iii) presents the evidence, challenges and strategies for bidirectional screening based on field studies to implement the framework and (iv) finally presents suggestions on how diabetes care delivery may benefit from the lessons of the TB DOTS approach and public health principles for structured care delivery.
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Affiliation(s)
- Anil Kapur
- World Diabetes Foundation, Gentofte, Denmark.
| | - Anthony D Harries
- International Union Against Tuberculosis and Lung Diseases, Paris, France; London School of Hygiene and Tropical Medicine, London, UK
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19
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Rysä J, Buler M, Savolainen MJ, Ruskoaho H, Hakkola J, Hukkanen J. Pregnane X receptor agonists impair postprandial glucose tolerance. Clin Pharmacol Ther 2013; 93:556-63. [PMID: 23588309 DOI: 10.1038/clpt.2013.48] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
We conducted a randomized, open, placebo-controlled crossover trial to investigate the effects of the pregnane X receptor (PXR) agonist rifampin on an oral glucose tolerance test (OGTT) in 12 healthy volunteers. The subjects were administered 600 mg rifampin or placebo once daily for 7 days, and OGTT was performed on the eighth day. The mean incremental glucose and insulin areas under the plasma concentration-time curves (AUC(incr)) increased by 192% (P = 0.008) and 45% (P = 0.031), respectively. The fasting glucose, insulin, and C-peptide, and the homeostasis model assessment for insulin resistance, were not affected. The glucose AUC(incr) during OGTT was significantly increased in rats after 4-day treatment with pregnenolone 16α-carbonitrile (PCN), an agonist of the rat PXR. The hepatic level of glucose transporter 2 (Glut2) mRNA was downregulated by PCN. In conclusion, both human and rat PXR agonists elicited postprandial hyperglycemia, suggesting a detrimental role of PXR activation on glucose tolerance.
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Affiliation(s)
- J Rysä
- Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, Oulu, Finland
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20
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Cheikh Rouhou M, Rheault I, Haddad S. Modulation of trichloroethylene in vitro metabolism by different drugs in rats. Toxicol In Vitro 2013; 27:34-43. [DOI: 10.1016/j.tiv.2012.10.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Revised: 09/10/2012] [Accepted: 10/08/2012] [Indexed: 11/26/2022]
Affiliation(s)
- Mouna Cheikh Rouhou
- TOXEN, Département des Sciences Biologiques, Université du Québec à Montréal, CP 8888 Succ Centre-ville, Montreal, Canada H3C 3P8
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21
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Drug interactions with oral antidiabetic agents: pharmacokinetic mechanisms and clinical implications. Trends Pharmacol Sci 2012; 33:312-22. [PMID: 22475684 DOI: 10.1016/j.tips.2012.03.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Revised: 02/27/2012] [Accepted: 03/02/2012] [Indexed: 12/21/2022]
Abstract
There is a growing epidemic of type 2 diabetes (T2DM), and it is associated with various comorbidities. Patients with T2DM are usually treated with multiple drugs, and are therefore at an increased risk of harmful drug-drug interactions (DDIs). Several potentially life-threatening DDIs concerning oral antidiabetic drugs have been identified. This has mostly been initiated by case reports but, more recently, the understanding of their mechanisms has greatly increased. In this article, we review the pharmacokinetic DDIs concerning oral antidiabetics, including metformin, sulfonylureas, meglitinide analogs, thiazolidinediones and dipeptidyl peptidase-4 inhibitors, and the underlying mechanistic basis that can help to predict and prevent DDIs. In particular, the roles of membrane transporters and cytochrome P450 (CYP) enzymes in these DDIs are discussed.
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Abdelmoneim AS, Hasenbank SE, Seubert JM, Brocks DR, Light PE, Simpson SH. Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Diabetes Obes Metab 2012; 14:130-8. [PMID: 21923736 DOI: 10.1111/j.1463-1326.2011.01496.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIM Insulin secretagogues promote insulin release by binding to sulfonylurea receptors on pancreatic β-cells (SUR1). However, these drugs also bind to receptor isoforms on cardiac myocytes (SUR2A) and vascular smooth muscle (SUR2B). Binding to SUR2A/SUR2B may inhibit ischaemic preconditioning, an endogenous protective mechanism enabling cardiac tissue to survive periods of ischaemia. This study was designed to identify insulin secretagogues that selectively bind to SUR1 when given at therapeutic doses. METHODS Using accepted systematic review methods, three electronic databases were searched from inception to 13 June 2011. Original studies measuring the half-maximal inhibitory concentration (IC(50)) for an insulin secretagogue on K(ATP) channels using standard electrophysiological techniques were included. Steady-state concentrations (C(SS)) were estimated from the usual oral dose and clearance values for each drug. RESULTS Data were extracted from 27 studies meeting all inclusion criteria. IC(50) values for SUR1 were below those for SUR2A/SUR2B for all insulin secretagogues and addition of C(SS) values identified three distinct patterns. The C(SS) for gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values for SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic receptors. The C(SS) for glimepiride and glyburide (glibenclamide) was above IC(50) values for all three isoforms, suggesting these drugs are non-selective. Tolbutamide and repaglinide may have partial pancreatic receptor selectivity because IC(50) values for SUR1 and SUR2A/SUR2B overlapped somewhat, with the C(SS) in the midst of these values. CONCLUSIONS Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.
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MESH Headings
- ATP-Binding Cassette Transporters/drug effects
- ATP-Binding Cassette Transporters/metabolism
- Animals
- Carbamates/adverse effects
- Cardiovascular Diseases/chemically induced
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Cricetinae
- Cyclohexanes/adverse effects
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/metabolism
- Gliclazide/adverse effects
- Glipizide/adverse effects
- Glyburide/adverse effects
- Humans
- Hypoglycemic Agents/adverse effects
- Hypoglycemic Agents/pharmacology
- Ischemic Preconditioning, Myocardial
- Isoindoles/adverse effects
- Mice
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/physiopathology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Nateglinide
- Phenylalanine/adverse effects
- Phenylalanine/analogs & derivatives
- Piperidines/adverse effects
- Potassium Channels, Inwardly Rectifying/drug effects
- Potassium Channels, Inwardly Rectifying/metabolism
- Rats
- Receptors, Drug/drug effects
- Receptors, Drug/metabolism
- Risk Factors
- Sulfonylurea Compounds/adverse effects
- Sulfonylurea Receptors
- Tolbutamide/adverse effects
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Affiliation(s)
- A S Abdelmoneim
- Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry/Pharmacy Centre, University of Alberta, Edmonton, Alberta, Canada
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23
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Chandrasekara H, Hardy K. 'The tubercular diabetic'. Clin Med (Lond) 2011; 11:628; author reply 628. [PMID: 22268328 PMCID: PMC4952355 DOI: 10.7861/clinmedicine.11-6-628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Bolhuis MS, Panday PN, Pranger AD, Kosterink JGW, Alffenaar JWC. Pharmacokinetic drug interactions of antimicrobial drugs: a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams. Pharmaceutics 2011; 3:865-913. [PMID: 24309312 PMCID: PMC3857062 DOI: 10.3390/pharmaceutics3040865] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2011] [Revised: 10/26/2011] [Accepted: 11/09/2011] [Indexed: 12/17/2022] Open
Abstract
Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug interactions of the commonly prescribed antimicrobial drugs oxazolidinones, rifamycines, macrolides, fluoroquinolones, and beta-lactams, focusing on systematic research. We describe drug-food and drug-drug interaction studies in humans, affecting antimicrobial drugs as well as concomitantly administered drugs. Since knowledge about mechanisms is of paramount importance for adequate management of drug interactions, the most plausible underlying mechanism of the drug interaction is provided when available. This overview can be used in daily practice to support the management of pharmacokinetic drug interactions of antimicrobial drugs.
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Affiliation(s)
- Mathieu S Bolhuis
- Department of Hospital and Clinical Pharmacy, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands.
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25
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Ruslami R, Aarnoutse RE, Alisjahbana B, van der Ven AJAM, van Crevel R. Implications of the global increase of diabetes for tuberculosis control and patient care. Trop Med Int Health 2011; 15:1289-99. [PMID: 20955495 DOI: 10.1111/j.1365-3156.2010.02625.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To review the current knowledge about tuberculosis (TB) and diabetes, assessing the implication of the global increase of diabetes for TB control and patient care. METHODS Systematic literature review. RESULTS Using public databases, it can be estimated that 12.6% (95% CI 9.2-17.3%) of new TB cases in the 10 countries with the highest TB burden will be attributable to TB in 2030, a relative increase of 25.5% compared to 2010. Diabetes is associated with a higher age and body weight among patients with TB, but probably not with a specific clinical presentation of TB. Rifampicin hampers glycemic control by increasing the metabolism of most oral antidiabetic drugs, while diabetes patients may have lower concentrations of anti-TB drugs. This might be one factor contributing to higher TB treatment failure rates. CONCLUSIONS The global epidemic of diabetes has implications for control and treatment of TB. Prospective studies are needed to improve prevention, early detection and treatment of concomitant diabetes and TB, especially in developing countries.
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Affiliation(s)
- Rovina Ruslami
- Department of Pharmacology, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia
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26
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Shao H, Ren XM, Liu NF, Chen GM, Li WL, Zhai ZH, Wang DW. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. J Clin Pharm Ther 2010; 35:351-60. [PMID: 20831536 DOI: 10.1111/j.1365-2710.2009.01134.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND AND OBJECTIVE CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. METHODS Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography-tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. RESULTS AND DISCUSSION There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC(0-∞) and C(max) in group C were significantly higher [83.94 ± 40.41 vs. 16.39 ± 5.10 μg·h/mL (P = 0.000) and 1.50 ± 0.85 vs. 0.45 ± 0.18 μg/mL (P = 0.000)], and the oral clearance was significantly lower [1.17 ± 0.63 vs. 5.38 ± 1.86 L/h (P = 0.000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33.47 ± 12.39 vs. 19.34 ± 10.45 h), but the difference was not significant (P = 0.052). The increase in serum glucose level at 11 h after dosing (ΔC(glu11)) in group C was significantly higher than that of group A (-1.08 ± 0.42 vs. 0.22 ± 1.01 mmol/L, P = 0.022). The corresponding insulin levels showed no difference between the two groups. CONCLUSION CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.
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Affiliation(s)
- H Shao
- Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China
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27
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Tan B, Zhang YF, Chen XY, Zhao XH, Li GX, Zhong DF. The effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide in Chinese subjects. Eur J Clin Pharmacol 2009; 66:145-51. [PMID: 19847408 DOI: 10.1007/s00228-009-0736-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2009] [Accepted: 09/21/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To study the effects of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of glipizide. METHODS Eighteen healthy male subjects were divided into three groups according to their genotypes: group I, CYP2C9*1/*1 and CYP2C19 extensive metabolizers (EMs); group II, CYP2C9*1/*1 and CYP2C19 poor metabolizers (PMs); and group III, CYP2C9*1/*3 and CYP2C19 EMs. After a single dose of a 5-mg glipizide tablet, plasma concentrations of glipizide for a 36-h period were determined. Meanwhile, plasma glucose levels and plasma insulin levels were determined from 0 to 4 h after dosing. RESULTS The area under the plasma concentration-time curve (AUC(0-infinity)) was 2.0-fold higher and the oral clearance was 51.1% lower in group III than in group I. The change in fasting insulin level within 1 h (DeltaAUEC(insulin0-1h)) in group III was 3.8-fold higher than that in group I. The glipizide parameters in group II exhibited similar tendencies to those in group III. CONCLUSIONS These results suggest that CYP2C9 polymorphism significantly influences the pharmacokinetics and pharmacodynamics of glipizide, which needs to be considered in clinical practice. CYP2C19 polymorphism exhibits a tendency to influence the effects of glipizide, to a certain extent similarly to CYP2C9 polymorphism.
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Affiliation(s)
- Bo Tan
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Vormfelde SV, Brockmöller J, Bauer S, Herchenhein P, Kuon J, Meineke I, Roots I, Kirchheiner J. Relative impact of genotype and enzyme induction on the metabolic capacity of CYP2C9 in healthy volunteers. Clin Pharmacol Ther 2009; 86:54-61. [PMID: 19369937 DOI: 10.1038/clpt.2009.40] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Pharmacokinetics in individual subjects is determined by genes and environment. The relative contributions of enzyme induction and inherited genomic variation to cytochrome P450 enzyme 2C9 (CYP2C9) activity are unknown. In 130 volunteers, CYP2C9 activity was measured in vivo using tolbutamide as a probe drug. Tolbutamide was administered orally, and the pharmacokinetics of the drug was analyzed twice--before and after four doses of 450 mg rifampin. Mean total apparent clearances (Cl/F) in the genotype groups CYP2C9*1/*1, *1/*2, *1/*3, *2/*3, and *3/*3 before rifampin were 0.78, 0.74, 0.52, 0.40, and 0.13 l/h, respectively. After rifampin administration, these clearances increased in all genotype groups by a median factor of 1.9 (range 1.1-4.8). The combined effects of genes and environment could be predicted by a simple additive model. Thus, enzyme induction resulted in an approximately twofold difference in CYP2C9 activity, irrespective of the CYP2C9 genotypes. But the difference in activity levels between the CYP2C9*1/*1 and *3/*3 genotypes before the administration of rifampin was sixfold.
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Affiliation(s)
- S V Vormfelde
- Department of Clinical Pharmacology, University Medical Center of the Georg August University Göttingen, Göttingen, Germany
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29
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Yao Y, Han WW, Zhou YH, Li ZS, Li Q, Chen XY, Zhong DF. The metabolism of CYP2C9 and CYP2C19 for gliclazide by homology modeling and docking study. Eur J Med Chem 2009; 44:854-61. [DOI: 10.1016/j.ejmech.2008.04.015] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2007] [Revised: 04/15/2008] [Accepted: 04/23/2008] [Indexed: 11/17/2022]
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Probiotic treatment reduces blood glucose levels and increases systemic absorption of gliclazide in diabetic rats. Eur J Drug Metab Pharmacokinet 2008; 33:101-6. [PMID: 18777945 DOI: 10.1007/bf03191026] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The action of gliclazide, a sulphonylurea with beneficial extrapancreatic effects in diabetes, may be enhanced by administering probiotics. The aim of this study was to investigate the influence of probiotics on gliclazide pharmacokinetics and the effect of both probiotics and gliclazide on blood glucose levels in healthy and diabetic rats. Male Wistar rats (2 to 3 months, weight 350 +/- 50 g) were randomly allocated to 4 groups (n =10), two of which were treated with alloxan i.v. 30 mg/kg to induce diabetes. One group of healthy and one group of diabetic rats were then gavaged with probiotics (75 mg/kg) for three days after which a gliclazide suspension (20 mg/kg) was administered by gavage to all groups. Blood samples were collected from the tail vein at various time points for 10 hours post-administration for the determination of blood glucose and gliclazide serum concentrations. It was found that probiotic treatment had no effect on blood glucose levels in healthy rats, but it reduced them (up to 2-fold; p < 0.01) in diabetic rats. Probiotic treatment reduced gliclazide bioavailability in healthy rats (3-fold) whereas it increased gliclazide bioavailability in diabetic rats (2-fold; p < 0.01). Gliclazide had no effect on blood glucose levels in either healthy or diabetic rats despite the changes in its bioavailability. In conclusion, the probiotic treatment of diabetic rats increases gliclazide bioavailability and lowers blood glucose levels by insulin-independent mechanisms, suggesting that the administration of probiotics may be beneficial as adjunct therapy in the treatment of diabetes.
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Development and evaluation of an in vivo assay in Caenorhabditis elegans for screening of compounds for their effect on cytochrome P450 expression. J Biosci 2008; 33:269-77. [PMID: 18535361 DOI: 10.1007/s12038-008-0044-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Most drugs and xenobiotics induce the expression of cytochrome P450 (CYP) enzymes, which reduce the bioavailability of the inducer and/or co-administered drugs. Therefore, evaluation of new drug candidates for their effect on CYP expression is an essential step in drug development. The available methods for this purpose are expensive and not amenable to high-throughput screening. We developed a fluorescence-based in vivo assay using transgenic Caenorhabditis elegans worms that express the green fluorescent protein (GFP) under the control of various CYP promoters. Using this assay, we found striking similarities between the worm CYPs and their human orthologs in their response to treatment with various drugs. For example,the antibiotic rifampicin, one of the strongest inducers of the human gene CYP3A4, was the strongest inducer of the worm ortholog CYP13A7. Since worms can be easily grown in liquid medium in microtitre plates, the assay described in this paper is suitable for the screening of a large number of potential lead compounds in the drug discovery process.
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The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes. Eur J Drug Metab Pharmacokinet 2008; 33:137-42. [DOI: 10.1007/bf03191110] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Pharmacokinetics of rosuvastatin when coadministered with rifampicin in healthy males: A randomized, single-blind, placebo-controlled, crossover study. Clin Ther 2008; 30:1283-9. [DOI: 10.1016/s0149-2918(08)80052-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2008] [Indexed: 10/21/2022]
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Al-Salami H, Butt G, Tucker I, Skrbic R, Golocorbin-Kon S, Mikov M. Probiotic Pre-treatment Reduces Gliclazide Permeation (ex vivo) in Healthy Rats but Increases It in Diabetic Rats to the Level Seen in Untreated Healthy Rats. ACTA ACUST UNITED AC 2008; 1:35-41. [PMID: 20157366 PMCID: PMC2817444 DOI: 10.1111/j.1753-5174.2008.00006.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Aim To investigate the influence of probiotic pre-treatment on the permeation of the antidiabetic drug gliclazide in healthy and diabetic rats. Methods Wistar rats (age 2–3 months, weight 350 ± 50 g) were randomly allocated into one of 4 groups (N = 16 each group): healthy control, healthy probiotic, diabetic control, and diabetic probiotic. Probiotics (75 mg/kg, equal quantities of Lactobacillus acidophilus, Bifidobacterium lactis, and Lactobacillus rhamnosus) were administered twice a day for three days to the appropriate groups after diabetes had been induced with alloxan i.v. 30 mg/kg. Rats were sacrificed, ileal tissues mounted in Ussing chambers and gliclazide (200 µg/mL) was administered for the measurement of the mucosal to serosal absorption Jss(MtoS) and serosal to mucosal secretion Jss(StoM) of gliclazide. Results Treatment of healthy rats with probiotics reduced Jss(MtoS) of gliclazide from 1.2 ± 0.3 to 0.3 ± 0.1 µg/min/cm2 (P < 0.01) and increased Jss(StoM)from 0.6 ± 0.1 to 1.4 ± 0.3 (P < 0.01) resulting in net secretion while, in diabetic tissues, treatment with probiotics increased both Jss(MtoS) and Jss(StoM)fluxes of gliclazide to the comparable levels of healthy tissues resulting in net absorption. Discussion In healthy rats, the reduction in Jss(MtoS) after probiotics administration could be explained by the production of bacterial metabolites that upregulate the mucosal efflux drug transporters Mrp2 that control gliclazide transport. In diabetic rats, the restored fluxes of gliclazide after probiotic treatment, suggests the normalization of the functionality of the drug transporters resulting in a net absorption. Conclusion Probiotics may alter gliclazide transport across rat ileal tissue studied ex vivo.
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Affiliation(s)
- Hani Al-Salami
- School of Pharmacy, University of OtagoDunedin, New Zealand
| | - Grant Butt
- Department of Physiology, University of OtagoDunedin, New Zealand
| | - Ian Tucker
- School of Pharmacy, University of OtagoDunedin, New Zealand
| | - Ranko Skrbic
- Department of Pharmacology, Medical Faculty, University of Banja Luka, Save Mrkalja Banja LukaBosnia and Herzegovina
| | - Svetlana Golocorbin-Kon
- Department of Pharmacology, Medical Faculty, University of Banja Luka, Save Mrkalja Banja LukaBosnia and Herzegovina
| | - Momir Mikov
- School of Pharmacy, University of OtagoDunedin, New Zealand
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Kim KA, Park PW, Liu KH, Kim KB, Lee HJ, Shin JG, Park JY. Effect of rifampin, an inducer of CYP3A and P-glycoprotein, on the pharmacokinetics of risperidone. J Clin Pharmacol 2008; 48:66-72. [PMID: 18094221 DOI: 10.1177/0091270007309888] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The authors studied the effect of rifampin, a dual inducer of CYP3A and P-glycoprotein, on the pharmacokinetics and pharmacodynamics of risperidone in humans. Ten healthy male subjects were treated daily for 7 days with 600 mg rifampin or with placebo. On day 6, a single dose of 1 mg risperidone was administered. Plasma risperidone and 9-hydroxyrisperidone concentrations were measured. Rifampin significantly decreased the mean area under the plasma concentration-time curve by 51% for risperidone, by 43% for 9-hydroxyrisperidone, and by 45% for the active moieties (risperidone + 9-hydroxyrisperidone). Rifampin also decreased the peak plasma concentration of risperidone by 38%, 9-hydroxyrisperidone by 46%, and the active moieties by 41%. The apparent oral clearance of risperidone approximately doubled after rifampin treatment. Thus, rifampin reduced the exposure to risperidone, probably because of a decrease in its bioavailability through the induction of CYP3A and probably P-glycoprotein.
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Affiliation(s)
- Kyoung-Ah Kim
- Department of Clinical Pharmacology & Toxicology, Anam Hospital, Korea University College of Medicine, 126-1, Anam-dong 5-ga, Sungbuk-gu, Seoul 136-705, Korea
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Abstract
Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes as well as the P-glycoprotein transport system. Several examples of well-documented clinically significant interactions include warfarin, oral contraceptives, cyclosporine, itraconazole, digoxin, verapamil, nifedipine, simvastatin, midazolam, and human immunodeficiency virus-related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Examples of clinically relevant interactions demonstrated by recent reports include everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam. To avoid a decreased therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Studies and cases of rifampin drug interactions continue to increase rapidly. This review is a timely reminder to clinicians to be vigilant.
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Xu H, Williams KM, Liauw WS, Murray M, Day RO, McLachlan AJ. Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide. Br J Pharmacol 2008; 153:1579-86. [PMID: 18204476 PMCID: PMC2437900 DOI: 10.1038/sj.bjp.0707685] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2007] [Revised: 12/05/2007] [Accepted: 12/12/2007] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND AND PURPOSE Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.
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Affiliation(s)
- H Xu
- Faculty of Pharmacy, University of Sydney Sydney, New South Wales, Australia
| | - K M Williams
- St Vincent's Clinical Trial Centre and University of New South Wales Sydney, New South Wales, Australia
| | - W S Liauw
- St Vincent's Clinical Trial Centre and University of New South Wales Sydney, New South Wales, Australia
| | - M Murray
- Faculty of Pharmacy, University of Sydney Sydney, New South Wales, Australia
| | - R O Day
- St Vincent's Clinical Trial Centre and University of New South Wales Sydney, New South Wales, Australia
| | - A J McLachlan
- Faculty of Pharmacy, University of Sydney Sydney, New South Wales, Australia
- Centre for Education and Research on Ageing, Concord Hospital Sydney, New South Wales, Australia
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Del Guerra S, Grupillo M, Masini M, Lupi R, Bugliani M, Torri S, Boggi U, Del Chiaro M, Vistoli F, Mosca F, Del Prato S, Marchetti P. Gliclazide protects human islet beta-cells from apoptosis induced by intermittent high glucose. Diabetes Metab Res Rev 2007; 23:234-8. [PMID: 16952202 DOI: 10.1002/dmrr.680] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Decreased beta-cell mass, mainly due to apoptosis, is crucial for the development and progression of type 2 diabetes. Chronic exposure to high glucose levels is a probable underlying mechanism, whereas the role of oral anti-diabetic agents (sulphonylureas in particular) is still unsettled. METHODS To directly investigate more on such issues, we prepared isolated human islets, which were then cultured for 5 days in continuous normal glucose concentration (NG, 5.5 mmol/L) or normal and high (HG, 16.7 mmol/L) glucose levels (alternating every 24 h), with or without the addition of therapeutical concentration (10 micromol L) of gliclazide or glibenclamide. RESULTS Intermittent high glucose caused a significant decrease of glucose-stimulated insulin secretion, which was not further affected by either sulphonylurea. Apoptosis, as assessed by electron microscopy, was also significantly increased by alternating high glucose exposure, which was accompanied by altered mitochondria morphology and density volume, and increased concentrations of nitrotyrosine, a marker of oxidative stress. Gliclazide, but not glibenclamide, was able to significantly reduce high glucose induced apoptosis, mitochondrial alterations, and nitrotyrosine concentration increase. CONCLUSION Therefore, gliclazide protected human beta-cells from apoptosis induced by intermittent high glucose, and this effect was likely to be due, at least in part, to the anti-oxidant properties of the molecule.
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Affiliation(s)
- S Del Guerra
- Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
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Zhang Y, Si D, Chen X, Lin N, Guo Y, Zhou H, Zhong D. Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics of gliclazide MR in Chinese subjects. Br J Clin Pharmacol 2007; 64:67-74. [PMID: 17298483 PMCID: PMC2000619 DOI: 10.1111/j.1365-2125.2007.02846.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
AIMS To investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics of gliclazide modified release (MR) in healthy Chinese subjects. METHODS In a single-dose pharmacokinetic study, 24 healthy male subjects with various CYP2C9 and CYP2C19 genotypes received an oral dose of 30 mg gliclazide MR and plasma was sampled for 72 h postdose. In a multiple-dose pharmacokinetic study, 17 other CYP2C9*1 homozygotes with various CYP2C19 genotypes received 30 mg gliclazide MR once daily for 6 days and plasma was sampled after the last dose. The plasma concentrations of gliclazide were measured using a validated LC/MS/MS method. CYP2C9 and CYP2C19 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS In the single-dose study, no significant difference in any pharmacokinetic parameters was found in CYP2C9*1/*1, *1/*3 and *1/*13 subjects. In contrast, the AUC(0-infinity) of gliclazide was significantly increased by 3.4-fold [95% confidence interval (CI) 2.5, 4.7; P < 0.01] in CYP2C19 poor metabolizer (PM) subjects compared with CYP2C19*1 homozygotes. The half-life (t(1/2)) was prolonged from 15.1 to 44.5 h (P < 0.01). Similar differences were found in the multiple-dose study. The parameters of gliclazide AUC(ss), AUC(0-infinity) and C(max) were 3.4-fold (95% CI 2.9, 4.0), 4.5-fold (95% CI 3.8, 5.4) and 2.9-fold (95% CI 2.4, 3.4) increased (P < 0.01) in CYP2C19 PM subjects, respectively, compared with CYP2C19*1 homozygotes, and t(1/2) was increased from 13.5 to 24.6 h (P < 0.01). CONCLUSIONS The pharmacokinetics of gliclazide MR are affected mainly by CYP2C19 genetic polymorphism instead of CYP2C9 genetic polymorphism.
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Affiliation(s)
- Yifan Zhang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Abstract
Because management of type 2 diabetes mellitus usually involves combined pharmacological therapy to obtain adequate glucose control and treatment of concurrent pathologies (especially dyslipidaemia and arterial hypertension), drug-drug interactions must be carefully considered with antihyperglycaemic drugs. Additive glucose-lowering effects have been extensively reported when combining sulphonylureas (or the new insulin secretagogues, meglitinide derivatives, i.e. nateglinide and repaglinide) with metformin, sulphonylureas (or meglitinide derivatives) with thiazolidinediones (also called glitazones) and the biguanide compound metformin with thiazolidinediones. Interest in combining alpha-glucosidase inhibitors with either sulphonylureas (or meglitinide derivatives), metformin or thiazolidinediones has also been demonstrated. These combinations result in lower glycosylated haemoglobin (HbA(1c)), fasting glucose and postprandial glucose levels than with either monotherapy. Even if modest pharmacokinetic interferences have been reported with some combinations, they do not appear to have important clinical consequences. No significant adverse effects, except a higher risk of hypoglycaemic episodes that may be attributed to better glycaemic control, occur with any combination. Challenging the classical dual therapy with sulphonylurea plus metformin, there is a recent trend to use alternative dual combinations (sulphonylurea plus thiazolidinedione or metformin plus thiazolidinedione). In addition, triple therapy with the addition of a thiazolidinedione to the metformin-sulphonylurea combination has been recently evaluated and allows glucose targets to be reached before insulin therapy is considered. This triple therapy appears to be safe, with no deleterious drug-drug interactions being reported so far.Potential interferences may also occur between glucose-lowering agents and other drugs, and such drug-drug interactions may have important clinical implications. Relevant pharmacological agents are those that are widely coadministered in diabetic patients (e.g. lipid-lowering agents, antihypertensive agents); those that have a narrow efficacy/toxicity ratio (e.g. digoxin, warfarin); or those that are known to induce (rifampicin [rifampin]) or inhibit (fluconazole) the cytochrome P450 (CYP) system. Metformin is currently a key compound in the pharmacological management of type 2 diabetes, used either alone or in combination with other antihyperglycaemics. There are no clinically relevant metabolic interactions with metformin, because this compound is not metabolised and does not inhibit the metabolism of other drugs. In contrast, sulphonylureas, meglitinide derivatives and thiazolidinediones are extensively metabolised in the liver via the CYP system and thus, may be subject to drug-drug metabolic interactions. Many HMG-CoA reductase inhibitors (statins) are also metabolised via the CYP system. Even if modest pharmacokinetic interactions may occur, it is not clear whether drug-drug interactions between oral antihyperglycaemic agents and statins may have clinical consequences regarding both efficacy and safety. In contrast, a marked pharmacokinetic interference has been reported between gemfibrozil and repaglinide and, to a lesser extent, between gemfibrozil and rosiglitazone. This leads to a drastic increase in plasma concentrations of each antihyperglycaemic agent when they are coadministered with the fibric acid derivative, and an increased risk of adverse effects. Some antihypertensive agents may favour hypoglycaemic episodes when co-prescribed with sulphonylureas or meglitinide derivatives, especially ACE inhibitors, but this effect seems to result from a pharmacodynamic drug-drug interaction rather than from a pharmacokinetic drug-drug interaction. No, or only modest, interferences have been described with glucose-lowering agents and other pharmacological compounds such as digoxin or warfarin. The effects of inducers or inhibitors of CYP isoenzymes on the metabolism and pharmacokinetics of the glucose-lowering agents of each pharmacological class has been tested. Significantly increased (with CYP inhibitors) or decreased (with CYP inducers) plasma levels of sulphonylureas, meglitinide derivatives and thiazolidinediones have been reported in healthy volunteers, and these pharmacokinetic changes may lead to enhanced or reduced glucose-lowering action, and thus hypoglycaemia or worsening of metabolic control, respectively. In addition, some case reports have evidenced potential drug-drug interactions with various antihyperglycaemic agents that are usually associated with a higher risk of hypoglycaemia.
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Affiliation(s)
- André J Scheen
- Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, Liège, Belgium.
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Niwa T, Honda S, Shirakawa K, Imamura Y, Osaki S, Takagi A. [Drug interaction of fluvoxamine, a selective serotonin reuptake inhibitor]. Nihon Yakurigaku Zasshi 2006; 128:93-103. [PMID: 16943644 DOI: 10.1254/fpj.128.93] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
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Jaakkola T, Backman JT, Neuvonen M, Laitila J, Neuvonen PJ. Effect of rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol 2006; 61:70-8. [PMID: 16390353 PMCID: PMC1884976 DOI: 10.1111/j.1365-2125.2005.02515.x] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
AIMS The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans. METHODS In a randomized, two-phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M-IV and M-III into urine were measured up to 48 h. RESULTS Rifampicin decreased the mean total area under the plasma concentration-time curve (AUC(0-infinity)) of pioglitazone by 54% (range 20-66%; P = 0.0007; 95% confidence interval -78 to -30%) and shortened its dominant elimination half-life (t(1/2)) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (C(max)) or time to peak (t(max)) was observed. Rifampicin increased the apparent formation rate of M-IV and shortened its t(max) (P < 0.01). It also decreased the AUC(0-infinity) of M-IV (by 34%; P = 0.0055) and M-III (by 39%; P = 0.0026), shortened their t1/2 (M-IV by 50%; P = 0.0008, and M-III by 55%; P = 0.0016) and increased the AUC(0-infinity) ratios of M-IV and M-III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M-IV/pioglitazone and M-III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M-XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M-XI to pioglitazone by 240% (P = 0.0020). CONCLUSIONS Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.
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Affiliation(s)
- Tiina Jaakkola
- Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
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Lin JH. CYP Induction-Mediated Drug Interactions: in Vitro Assessment and Clinical Implications. Pharm Res 2006; 23:1089-116. [PMID: 16718615 DOI: 10.1007/s11095-006-0277-7] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2005] [Accepted: 02/27/2006] [Indexed: 01/31/2023]
Abstract
Cytochrome P450 (CYP) induction-mediated interaction is one of the major concerns in clinical practice and for the pharmaceutical industry. There are two major issues associated with CYP induction: a reduction in therapeutic efficacy of comedications and an induction in reactive metabolite-induced toxicity. Because CYP induction is a metabolic liability in drug therapy, it is highly desirable to develop new drug candidates that are not potent CYP inducer to avoid the potential of CYP induction-mediated drug interactions. For this reason, today, many drug companies routinely include the assessment of CYP induction at the stage of drug discovery as part of the selection processes of new drug candidates for further clinical development. The purpose of this article is to review the molecular mechanisms of CYP induction and the clinical implications, including pharmacokinetic and pharmacodynamic consequences. In addition, factors that affect the degree of CYP induction and extrapolation of in vitro CYP induction data to in vivo situations will also be discussed. Finally, assessment of the potential of CYP induction at the drug discovery and development stage will be discussed.
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Affiliation(s)
- Jiunn H Lin
- Department of Preclinical Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania, USA.
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&NA;. Effects of drug-drug interactions involving oral antihyperglycaemics are, with the exception of hypoglycaemia, mostly clinically unimportant. DRUGS & THERAPY PERSPECTIVES 2006. [DOI: 10.2165/00042310-200622040-00008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
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Abstract
The sulphonylureas act by triggering insulin release from the pancreatic beta cell. A specific site on the adenosine triphosphate (ATP)-sensitive potassium channels is occupied by sulphonylureas leading to closure of the potassium channels and subsequent opening of calcium channels. This results in exocytosis of insulin. The meglitinides are not sulphonylureas but also occupy the sulphonylurea receptor unit coupled to the ATP-sensitive potassium channel. Glibenclamide (glyburide), gliclazide, glipizide and glimepiride are the primary sulphonylureas in current clinical use for type 2 diabetes mellitus. Glibenclamide has a higher frequency of hypoglycaemia than the other agents. With long-term use, there is a progressive decrease in the effectiveness of sulphonylureas. This loss of effect is the result of a reduction in insulin-producing capacity by the pancreatic beta cell and is also seen with other antihyperglycaemic agents. The major adverse effect of sulphonylureas is hypoglycaemia. There is a theoretical concern that sulphonylureas may affect cardiac potassium channels resulting in a diminished response to ischaemia. There are now many choices for initial therapy of type 2 diabetes in addition to sulphonylureas. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms. Disaccharidase inhibitors reduce rapid carbohydrate absorption. No single agent appears capable of achieving target glucose levels in the majority of patients with type 2 diabetes. Combinations of agents are successful in lowering glycosylated haemoglobin levels more than with a single agent. Sulphonylureas are particularly beneficial when combined with agents such as metformin that decrease insulin resistance. Sulphonylureas can also be given with a basal insulin injection to provide enhanced endogenous insulin secretion after meals. Sulphonylureas will continue to be used both primarily and as part of combined therapy for most patients with type 2 diabetes.
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Affiliation(s)
- Marc Rendell
- Creighton Diabetes Center, 601 North 30th Street, Omaha, NE 68131, USA.
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