• ABC pumps
• Drug transport
• Drug-drug interaction
• Liver pharmacology
• SLC transporters

• Humans
• Liver Diseases/metabolism
• Liver Diseases/drug therapy
• Liver/metabolism
• Animals
• Drug Interactions/physiology
• Pharmaceutical Preparations/metabolism
• Biological Transport/physiology
• Membrane Transport Proteins/metabolism
• Membrane Transport Proteins/genetics

• P-glycoprotein
• TB
• angiogenesis
• drug efflux
• granuloma
• macrophages
• multidrug resistance

• Humans
• Antitubercular Agents/pharmacology
• Antitubercular Agents/therapeutic use
• Animals
• ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors
• ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
• Tuberculosis, Multidrug-Resistant/drug therapy

• Autophagy
• Coinfections
• Comorbidity
• Diabetes mellitus
• Drug-drug interactions
• Treatment challenges
• Tuberculosis

• Organic Cation Transporter 1/metabolism
• Organic Cation Transport Proteins
• Biological Transport
• Protein Binding
• Cations
• Organic Cation Transporter 2/metabolism

• Universitätsmedizin Göttingen
• Deutsche Forschungsgemeinschaft

• China Academy of Chinese Medical Sciences

• 3HP
• HIV
• N-acetyltransferase 2
• dolutegravir
• isoniazid
• latent tuberculosis infection
• pharmacokinetics
• rifapentine

• Adult
• Humans
• Antitubercular Agents/therapeutic use
• Arylamine N-Acetyltransferase
• Body Weight
• Drug Therapy, Combination
• HIV
• HIV Infections/drug therapy
• Isoniazid/therapeutic use
• Latent Tuberculosis/drug therapy

• D43 TW009337 FIC NIH HHS
• K24 AI150349 NIAID NIH HHS
• UM1 AI154463 NIAID NIH HHS
• UNITAID
• HHS | NIH | Fogarty International Center (FIC)
• HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

• antituberculosis
• clofazimine
• membrane transporter
• substrate characterization

The Novel Organic Cation Transporter, OCTN1, is the first member of the OCTN subfamily; it belongs to the wider Solute Carrier family SLC22, which counts many members including cation and anion organic transporters. The tertiary structure has not been resolved for any cation organic transporter. The functional role of OCNT1 is still not well assessed despite the many functional studies so far conducted. The lack of a definitive identification of OCTN1 function can be attributed to the different experimental systems and methodologies adopted for studying each of the proposed ligands. Apart from the contradictory data, the international scientific community agrees on a role of OCTN1 in protecting cells and tissues from oxidative and/or inflammatory damage. Moreover, the involvement of this transporter in drug interactions and delivery has been well clarified, even though the exact profile of the transported/interacting molecules is still somehow confusing. Therefore, OCTN1 continues to be a hot topic in terms of its functional role and structure. This review focuses on the most recent advances on OCTN1 in terms of functional aspects, physiological roles, substrate specificity, drug interactions, tissue expression, and relationships with pathology.

• acetylcholine
• cancer
• carnitine
• ergothioneine
• health
• inflammation
• oxidative stress
• pharmacology

• Acetylation
• Animals
• Binding Sites
• Biological Transport
• Biomarkers
• Disease Susceptibility
• Drug Interactions
• Ergothioneine/metabolism
• Gene Expression Regulation/drug effects
• Gene Knockdown Techniques
• Humans
• Models, Molecular
• Molecular Conformation
• Organ Specificity
• Organic Cation Transport Proteins/chemistry
• Organic Cation Transport Proteins/genetics
• Organic Cation Transport Proteins/metabolism
• Protein Binding
• Structure-Activity Relationship
• Symporters/chemistry
• Symporters/genetics
• Symporters/metabolism

• SLC22A15
• SLC22A4
• brain
• ergothioneine transporter
• erythrocytes
• macrophages
• mass spectrometry
• monocytes
• neutrophils
• substrate profile

• Biological Transport, Active/physiology
• Biotransformation/physiology
• Dose-Response Relationship, Drug
• Drug Dosage Calculations
• Female
• HEK293 Cells
• Humans
• Metabolic Clearance Rate
• Organic Anion Transporters/classification
• Organic Anion Transporters/metabolism
• Pharmaceutical Preparations/classification
• Pharmaceutical Preparations/metabolism
• Pharmacokinetics
• Pregnancy
• Pregnancy Trimesters/drug effects
• Pregnancy Trimesters/metabolism
• Renal Elimination/physiology
• Reproducibility of Results

• P01 DA032507 NIDA NIH HHS

• Animals
• Cell Culture Techniques
• Gills
• Hydrogen-Ion Concentration
• Ibuprofen
• Pharmaceutical Preparations
• Propranolol
• Water

• G1000081/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research
• BB/M014827/1 Biotechnology and Biological Sciences Research Council

To date, information on the ontogeny of renal transporters is limited. Here, we propose to estimate the in vivo functional ontogeny of transporters using a combined population pharmacokinetic (popPK) and physiology-based pharmacokinetic (PBPK) modeling approach called popPBPK. Clavulanic acid and amoxicillin were used as probes for glomerular filtration, combined glomerular filtration, and active secretion through OAT1,3, respectively. The predictive value of the estimated OAT1,3 ontogeny function was assessed by PBPK predictions of renal clearance (CL_R) of other OAT1,3 substrates: cefazolin and piperacillin. Individual CL_Rpost-hoc values, obtained from a published popPK model on the concomitant use of clavulanic acid and amoxicillin in critically ill children between 1 month and 15 years, were used as dependent variables in the popPBPK analysis. CL_R was re-parameterized according to PBPK principles, resulting in the estimation of OAT1,3-mediated intrinsic clearance (CL_{int,OAT1,3,invivo}) and its ontogeny. CL_{int,OAT1,3,invivo} ontogeny was described by a sigmoidal function, reaching half of adult level around 7 months of age, comparable to findings based on renal transporter-specific protein expression data. PBPK-based CL_R predictions including this ontogeny function were reasonably accurate for piperacillin in a similar age range (2.5 months–15 years) as well as for cefazolin in neonates as compared to published data (%RMSPE of 21.2 and 22.8%, respectively and %PE within ±50%). Using this novel approach, we estimated an in vivo functional ontogeny profile for CL_{int,OAT1,3,invivo} that yields accurate CL_R predictions for different OAT1,3 substrates across different ages. This approach deserves further study on functional ontogeny of other transporters.

• OAT1,3
• Pediatrics
• Population PK
• ontogeny
• physiology-based PK

Organic Cation Transporter 1 (OCT1, gene symbol: SLC22A1) is predominately expressed in human liver, localized in the basolateral membrane of hepatocytes and facilitates the uptake of endogenous compounds (e.g. serotonin, acetylcholine, thiamine), and widely prescribed drugs (e.g. metformin, fenoterol, morphine). Furthermore, exogenous compounds such as MPP⁺, ASP⁺ and Tetraethylammonium can be used as prototypic substrates to study the OCT1-mediated transport in vitro. Single-transfected cell lines recombinantly overexpressing OCT1 (e.g., HEK-OCT1) were established to study OCT1-mediated uptake and to evaluate transporter-mediated drug-drug interactions in vitro. Furthermore, double-transfected cell models simultaneously overexpressing basolaterally localized OCT1 together with an apically localized export protein have been established. Most of these cell models are based on polarized grown MDCK cells and can be used to analyze transcellular transport, mimicking the transport processes e.g. during the hepatobiliary elimination of drugs. Multidrug and toxin extrusion protein 1 (MATE1, gene symbol: SLC47A1) and the ATP-driven efflux pump P-glycoprotein (P-gp, gene symbol: ABCB1) are both expressed in the canalicular membrane of human hepatocytes and are described as transporters of organic cations. OCT1 and MATE1 have an overlapping substrate spectrum, indicating an important interplay of both transport proteins during the hepatobiliary elimination of drugs. Due to the important role of OCT1 for the transport of endogenous compounds and drugs, in vitro cell systems are important for the determination of the substrate spectrum of OCT1, the understanding of the molecular mechanisms of polarized transport, and the investigation of potential drug-drug interactions. Therefore, the aim of this review article is to summarize the current knowledge on cell systems recombinantly overexpressing human OCT1.

• HEK 293
• MATE1
• MDCK cell line
• OCT1
• P-glycoprotein
• SLC22A1 (OCT1)
• double-transfected cell line
• single-transfected cell line

• Animals
• Fishes
• Fresh Water
• Gills/chemistry
• Ibuprofen
• Water Pollutants, Chemical/analysis

• G1000081/1 National Centre for the Replacement, Refinement and Reduction of Animals in Research
• BB/M014827/1 Biotechnology and Biological Sciences Research Council

The interaction between drugs and various transporters is one of the decisive factors that affect the pharmacokinetics and pharmacodynamics of drugs. The organic cation transporter 1 (OCT1) is a member of the Solute Carrier 22A (SLC22A) family that plays a vital role in the membrane transport of organic cations including endogenous substances and xenobiotics. This article mainly discusses the drug-drug interactions (DDIs) mediated by OCT1 and their clinical significance.

• OCT1
• drug-drug interaction
• inhibitor
• organic cation transporters
• substrate

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen.

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

• antituberculosis drugs
• dose optimization
• pediatric
• population pharmacokinetics
• tuberculosis meningitis

Enalaprilat is the active metabolite of enalapril, a widely used antihypertension drug. The human organic anion transporter 3 (OAT3), which is highly expressed in the kidney, plays a critical role in the renal clearance of many drugs. While urinary excretion is the primary elimination route of enalaprilat, direct involvement of OAT3 has not been reported so far. In the present study, OAT3-mediated uptake of enalaprilat was first characterized, and the inhibition of OAT3 transport activity was then examined for a number of flavonoid and drug molecules with diverse structures. A varying degree of inhibition potency was demonstrated for flavonoids, with IC₅₀ values ranging from 0.03 to 22.6 µM against OAT3 transport activity. In addition, commonly used drugs such as urate transporter 1 (URAT1) inhibitors also displayed potent inhibition on OAT3-mediated enalaprilat uptake. Pharmacophore and three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses revealed the presence of a polar center and a hydrophobic region involved in OAT3-inhibitor binding. For the polar center, hydroxyl groups present in flavonoids could act as either hydrogen bond donors or acceptors and the number and position of hydroxyl groups were critical drivers for inhibition potency, while carboxyl groups present in some drugs could form ionic bridges with OAT3. The predicted inhibition potencies by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were correlated well with experimental IC₅₀ values. Taken together, the present study identified OAT3-mediated uptake of enalaprilat as an important mechanism for its renal clearance, which may be liable for drug-drug and herb-drug interactions. The established computational models revealed unique structural features for OAT3 inhibitors and could be used for structure-activity relationship (SAR) analysis of OAT3 inhibition. The clinical relevance of the inhibition of OAT3-mediated enalaprilat uptake warrants further investigation, particularly in populations where herbal remedies and drugs are used concomitantly.

• enalaprilat
• flavonoid
• herb-drug interaction
• organic anion transporter 3 (OAT3)
• three-dimensional quantitative structure-activity relationship

• Anti-Infective Agents/economics
• Anti-Infective Agents/metabolism
• Anti-Infective Agents/therapeutic use
• Antitubercular Agents/economics
• Antitubercular Agents/metabolism
• Antitubercular Agents/therapeutic use
• Communicable Diseases/drug therapy
• Communicable Diseases/economics
• Communicable Diseases/metabolism
• Drug Interactions/physiology
• Humans
• Poverty/economics
• Poverty/trends
• Treatment Outcome
• Tuberculosis/drug therapy
• Tuberculosis/economics
• Tuberculosis/metabolism