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Lemke J, Mengers N, Schmidt L, Schulig L, König S, Rosendahl P, Bartz FM, Garscha U, Bednarski PJ, Link A. Lead Optimization of Positive Allosteric K V7.2/3 Channel Modulators toward Improved Balance of Lipophilicity and Aqueous Solubility. J Med Chem 2025; 68:8377-8399. [PMID: 40198203 DOI: 10.1021/acs.jmedchem.4c03112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
The voltage-gated potassium channel KV7.2/3 is gaining attention for its association with several medical indications. While recently reported, potent compounds aimed to fill the therapeutic gap left by market-withdrawn activators, key physicochemical parameters did not meet the requirements of potential drug candidates. Targeting the membrane-located channel requires subtly balancing lipophilicity, activity, and aqueous solubility. This publication describes the lead optimization of a highly active compound toward optimized physicochemical parameters. Out of 42 newly synthesized compounds, 30 showed activity on KV7.2/3 channels, and 15 had also an increased solubility compared the to hit compound. The integration of a three-dimensional bulky structure and the probable onset of chameleonic behavior, led to a 20-fold solubility increase (S = 21.7 vs 1.1 μM) and only slightly reduced potency (pEC50 = 7.42 vs 7.96) for the lead. Additionally, the target engagement of the compound was theoretically enhanced by a reduction of membrane retention.
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Affiliation(s)
- Jana Lemke
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Nadine Mengers
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Louis Schmidt
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Lukas Schulig
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Stefanie König
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Pascal Rosendahl
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Frieda-Marie Bartz
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Ulrike Garscha
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Patrick J Bednarski
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
| | - Andreas Link
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, Greifswald 17489, Germany
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Beirow K, Schmidt C, Jürgen B, Schlüter R, Schweder T, Bednarski PJ. Investigation of TGF-α-overexpressing mouse hepatocytes (TAMH) cultured as spheroids for use in hepatotoxicity screening of drug candidates. J Appl Toxicol 2024; 44:272-286. [PMID: 37655636 DOI: 10.1002/jat.4538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 07/24/2023] [Accepted: 08/15/2023] [Indexed: 09/02/2023]
Abstract
The immortalized mouse liver cell line TAMH has been described as a valuable tool for studying hepatotoxic mechanisms, but until now, it has only been reported to grow as a monolayer in culture. However, culturing hepatocytes as three-dimensional (3D) spheroids has been shown to result in improved liver-specific functions (e.g., metabolic capacity) by better mimicking the in vivo environment. This approach may lead to more reliable detection of drug-induced liver injury (DILI) in the early phase of drug discovery, preventing post-marketing drug withdrawals. Here, we investigated the cultivation of TAMH as 3D spheroids, characterizing them with optical and transmission electron microscopy as well as analyzing their gene expression at mRNA level (especially drug-metabolizing enzymes) compared to TAMH monolayer. In addition, comparisons were made with spheroids grown from the human hepatoblastoma cell line HepG2, another current spheroid model. The results indicate that TAMH spheroids express hepatic structures and show elevated levels of some of the key phase I and II drug-metabolizing enzymes, in contrast to TAMH monolayer. The in vitro hepatotoxic potencies of the drugs acetaminophen and flupirtine maleate were found to be very similar between TAMH spheroidal and the monolayer cultures. Both the advantages and disadvantages of TAMH spheroids as an in vitro hepatotoxicity model compared to monolayer model are discussed.
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Affiliation(s)
- Kristin Beirow
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Christian Schmidt
- Department of Pharmaceutical Biotechnology Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Britta Jürgen
- Department of Pharmaceutical Biotechnology Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Rabea Schlüter
- Imaging Center of the Department of Biology, University of Greifswald, Greifswald, Germany
| | - Thomas Schweder
- Department of Pharmaceutical Biotechnology Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Patrick J Bednarski
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
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Wurm KW, Bartz FM, Schulig L, Bodtke A, Bednarski PJ, Link A. Replacing the oxidation-sensitive triaminoaryl chemotype of problematic K V 7 channel openers: Exploration of a nicotinamide scaffold. Arch Pharm (Weinheim) 2023; 356:e2200473. [PMID: 36395379 DOI: 10.1002/ardp.202200473] [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: 09/08/2022] [Revised: 10/13/2022] [Accepted: 10/18/2022] [Indexed: 11/18/2022]
Abstract
KV 7 channel openers have proven their therapeutic value in the treatment of pain as well as epilepsy and, moreover, they hold the potential to expand into additional indications with unmet medical needs. However, the clinically validated but meanwhile discontinued KV 7 channel openers flupirtine and retigabine bear an oxidation-sensitive triaminoraryl scaffold, which is suspected of causing adverse drug reactions via the formation of quinoid oxidation products. Here, we report the design and synthesis of nicotinamide analogs and related compounds that remediate the liability in the chemical structure of flupirtine and retigabine. Optimization of a nicotinamide lead structure yielded analogs with excellent KV 7.2/3 opening activity, as evidenced by EC50 values approaching the single-digit nanomolar range. On the other hand, weighted KV 7.2/3 opening activity data including inactive compounds allowed for the establishment of structure-activity relationships and a plausible binding mode hypothesis verified by docking and molecular dynamics simulations.
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Affiliation(s)
- Konrad W Wurm
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Frieda-Marie Bartz
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Lukas Schulig
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Anja Bodtke
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Patrick J Bednarski
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
| | - Andreas Link
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany
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Wurm KW, Bartz FM, Schulig L, Bodtke A, Bednarski PJ, Link A. Carba Analogues of Flupirtine and Retigabine with Improved Oxidation Resistance and Reduced Risk of Quinoid Metabolite Formation. ChemMedChem 2022; 17:e202200262. [PMID: 35687532 PMCID: PMC9541272 DOI: 10.1002/cmdc.202200262] [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] [Received: 05/11/2022] [Revised: 06/07/2022] [Indexed: 01/10/2023]
Abstract
The KV7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine‐induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. KV7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand‐based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved KV7.2/3 channel opening activity, indicated by an up to 13‐fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.
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Affiliation(s)
- Konrad W Wurm
- University of Greifswald: Universitat Greifswald, Institute of Pharmacy, GERMANY
| | - Frieda-Marie Bartz
- University of Greifswald: Universitat Greifswald, Institute of Pharmacy, GERMANY
| | - Lukas Schulig
- University of Greifswald: Universitat Greifswald, Institute of Pharmacy, GERMANY
| | - Anja Bodtke
- University of Greifswald: Universitat Greifswald, Institute of Pharmacy, GERMANY
| | - Patrick J Bednarski
- University of Greifswald: Universitat Greifswald, Institute of Pharmacy, GERMANY
| | - Andreas Link
- University of Greifswald, Institute of Pharmacy, F.-L.-Jahn-Str. 17, 17487, Greifswald, GERMANY
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Wurm K, Bartz FM, Schulig L, Bodtke A, Bednarski PJ, Link A. Modifications of the Triaminoaryl Metabophore of Flupirtine and Retigabine Aimed at Avoiding Quinone Diimine Formation. ACS OMEGA 2022; 7:7989-8012. [PMID: 35284765 PMCID: PMC8908504 DOI: 10.1021/acsomega.1c07103] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/08/2022] [Indexed: 05/09/2023]
Abstract
The potassium channel opening drugs flupirtine and retigabine have been withdrawn from the market due to occasional drug-induced liver injury (DILI) and tissue discoloration, respectively. While the mechanism underlying DILI after prolonged flupirtine use is not entirely understood, evidence indicates that both drugs are metabolized in an initial step to reactive ortho- and/or para-azaquinone diimines or ortho- and/or para-quinone diimines, respectively. Aiming to develop safer alternatives for the treatment of pain and epilepsy, we have attempted to separate activity from toxicity by employing a drug design strategy of avoiding the detrimental oxidation of the central aromatic ring by shifting oxidation toward the formation of benign metabolites. In the present investigation, an alternative retrometabolic design strategy was followed. The nitrogen atom, which could be involved in the formation of both ortho- or para-quinone diimines of the lead structures, was shifted away from the central ring, yielding a substitution pattern with nitrogen substituents in the meta position only. Evaluation of KV7.2/3 opening activity of the 11 new specially designed derivatives revealed surprisingly steep structure-activity relationship data with inactive compounds and an activity cliff that led to the identification of an apparent "magic methyl" effect in the case of N-(4-fluorobenzyl)-6-[(4-fluorobenzyl)amino]-2-methoxy-4-methylnicotinamide. This flupirtine analogue showed potent KV7.2/3 opening activity, being six times as active as flupirtine itself, and by design is devoid of the potential for azaquinone diimine formation.
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Zhang YM, Xu HY, Hu HN, Tian FY, Chen F, Liu HN, Zhan L, Pi XP, Liu J, Gao ZB, Nan FJ. Discovery of HN37 as a Potent and Chemically Stable Antiepileptic Drug Candidate. J Med Chem 2021; 64:5816-5837. [PMID: 33929863 DOI: 10.1021/acs.jmedchem.0c02252] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We previously reported that P-retigabine (P-RTG), a retigabine (RTG) analogue bearing a propargyl group at the nitrogen atom in the linker of RTG, displayed moderate anticonvulsant efficacy. Recently, our further efforts led to the discovery of HN37 (pynegabine), which demonstrated satisfactory chemical stability upon deleting the ortho liable -NH2 group and installing two adjacent methyl groups to the carbamate motif. HN37 exhibited enhanced activation potency toward neuronal Kv7 channels and high in vivo efficacy in a range of pre-clinical seizure models, including the maximal electroshock test and a 6 Hz model of pharmacoresistant limbic seizures. With its improved chemical stability, strong efficacy, and better safety margin, HN37 has progressed to clinical trial in China for epilepsy treatment.
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Affiliation(s)
- Yang-Ming Zhang
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, No. 39, Science and Technology Avenue, High-Tech Industrial Development Zone, Yantai City, Shandong 264000, China
| | - Hai-Yan Xu
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing City, Jiangsu 210023, China
| | - Hai-Ning Hu
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Fu-Yun Tian
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Fei Chen
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Hua-Nan Liu
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Li Zhan
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Xiao-Ping Pi
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Jie Liu
- Hainan Haiyao Company Ltd., No. 192, Nanhai Road, Xiuying District, Haikou City, Hainan 570311, China
| | - Zhao-Bing Gao
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Avenue, Qixia District, Nanjing City, Jiangsu 210023, China
| | - Fa-Jun Nan
- Chinese National Center for Drug Screening, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, No. 39, Science and Technology Avenue, High-Tech Industrial Development Zone, Yantai City, Shandong 264000, China
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Borgini M, Mondal P, Liu R, Wipf P. Chemical modulation of Kv7 potassium channels. RSC Med Chem 2021; 12:483-537. [PMID: 34046626 PMCID: PMC8128042 DOI: 10.1039/d0md00328j] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/01/2020] [Indexed: 01/10/2023] Open
Abstract
The rising interest in Kv7 modulators originates from their ability to evoke fundamental electrophysiological perturbations in a tissue-specific manner. A large number of therapeutic applications are, in part, based on the clinical experience with two broad-spectrum Kv7 agonists, flupirtine and retigabine. Since precise molecular structures of human Kv7 channel subtypes in closed and open states have only very recently started to emerge, computational studies have traditionally been used to analyze binding modes and direct the development of more potent and selective Kv7 modulators with improved safety profiles. Herein, the synthetic and medicinal chemistry of small molecule modulators and the representative biological properties are summarized. Furthermore, new therapeutic applications supported by in vitro and in vivo assay data are suggested.
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Affiliation(s)
- Matteo Borgini
- Department of Chemistry, University of Pittsburgh Pittsburgh PA 15260 USA
| | - Pravat Mondal
- Department of Chemistry, University of Pittsburgh Pittsburgh PA 15260 USA
| | - Ruiting Liu
- Department of Chemistry, University of Pittsburgh Pittsburgh PA 15260 USA
| | - Peter Wipf
- Department of Chemistry, University of Pittsburgh Pittsburgh PA 15260 USA
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Lawson K, Singh A, Kantsedikas I, Jenner CA, Austen DK. Flupirtine as a Potential Treatment for Fibromyalgia. JOURNAL OF EXPLORATORY RESEARCH IN PHARMACOLOGY 2021; 000:000-000. [DOI: 10.14218/jerp.2020.00043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
Electron transfer plays a vital role in drug metabolism and underlying toxicity mechanisms. Currently, pharmaceutical research relies on pharmacokinetics (PK) and absorption, distribution, metabolism, elimination and toxicity (ADMET) measurements to understand and predict drug reactions in the body. Metabolic stability (and toxicity) prediction in the early phases of the drug discovery and development process is key in identifying a suitable lead compound for optimisation. Voltammetric methods have the potential to overcome the significant barrier of new drug failure rates, by giving insight into phase I metabolism events which can have a direct bearing on the stability and toxicity of the parent drug being dosed. Herein, we report for the first time a data-mining investigation into the voltammetric behaviour of reported drug molecules and their correlation with metabolic stability (indirectly measured via t½), as a potential predictor of drug stability/toxicity in vivo. We observed an inverse relationship between oxidation potential and drug stability. Furthermore, we selected and prepared short- (<10 min) and longer-circulation (>2 h) drug molecules to prospectively survey the relationship between oxidation potential and stability.
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Wang J, Bwayi M, Florke Gee RR, Chen T. PXR-mediated idiosyncratic drug-induced liver injury: mechanistic insights and targeting approaches. Expert Opin Drug Metab Toxicol 2020; 16:711-722. [PMID: 32500752 PMCID: PMC7429329 DOI: 10.1080/17425255.2020.1779701] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 06/04/2020] [Indexed: 01/03/2023]
Abstract
INTRODUCTION The human liver is the center for drug metabolism and detoxification and is, therefore, constantly exposed to toxic chemicals. The loss of liver function as a result of this exposure is referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) is the primary regulator of the hepatic drug-clearance system, which plays a critical role in mediating idiosyncratic DILI. AREAS COVERED This review is focused on common mechanisms of PXR-mediated DILI and on in vitro and in vivo models developed to predict and assess DILI. It also provides an update on the development of PXR antagonists that may manage PXR-mediated DILI. EXPERT OPINION DILI can be caused by many factors, and PXR is clearly linked to DILI. Although emerging data illustrate how PXR mediates DILI and how PXR activity can be modulated, many questions concerning the development of effective PXR modulators remain. Future research should be focused on determining the mechanisms regulating PXR functions in different cellular contexts.
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Affiliation(s)
- Jingheng Wang
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Monicah Bwayi
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
| | - Rebecca R. Florke Gee
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
| | - Taosheng Chen
- Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
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Abstract
Cumulative research over several decades has implicated the involvement of reactive metabolites in many idiosyncratic adverse drug reactions (IADRs). Consequently, "avoidance" strategies have been inserted into drug discovery paradigms, which include the exclusion of structural alerts and possible termination of reactive metabolite-positive compounds. Several noteworthy examples where reactive metabolite-related liabilities have been resolved through structure-metabolism studies are presented herein. Considerable progress has also been made in addressing the limitations of the avoidance strategy and further refining the process of managing reactive metabolite issues in drug development. These efforts primarily stemmed from the observation that numerous drugs, which contain structural alerts and/or form reactive metabolites, are devoid of ADRs. The Perspective also dwells into an analysis of the structural alert/reactive metabolite concept with a discussion of risk mitigation tactics to support the progression of reactive metabolite-positive drug candidates.
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Affiliation(s)
- Amit S Kalgutkar
- Medicine Design, Pfizer Worldwide Research, Development and Medical, 1 Portland Street, Cambridge, Massachusetts 02139, United States
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Bock C, Surur AS, Beirow K, Kindermann MK, Schulig L, Bodtke A, Bednarski PJ, Link A. Sulfide Analogues of Flupirtine and Retigabine with Nanomolar K V 7.2/K V 7.3 Channel Opening Activity. ChemMedChem 2019; 14:952-964. [PMID: 30861620 DOI: 10.1002/cmdc.201900112] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Indexed: 12/18/2022]
Abstract
The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to the formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation toward the formation of more benign metabolites. Structure-activity relationship studies were performed to evaluate the KV 7.2/3 channel opening activity of 45 derivatives. Sulfide analogues were identified that are devoid of the risk of quinone formation, but possess potent KV 7.2/3 opening activity. For example, flupirtine analogue 3-(3,5-difluorophenyl)-N-(6-(isobutylthio)-2-(pyrrolidin-1-yl)pyridin-3-yl)propanamide (48) has 100-fold enhanced activity (EC50 =1.4 nm), a vastly improved toxicity/activity ratio, and the same efficacy as retigabine in vitro.
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Affiliation(s)
- Christian Bock
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Abdrrahman S Surur
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Kristin Beirow
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Markus K Kindermann
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Lukas Schulig
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Anja Bodtke
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Patrick J Bednarski
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
| | - Andreas Link
- Institute of Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489, Greifswald, Germany
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Abstract
The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration. Because the adverse effects seem unrelated to the mode of action, it is likely, that both drugs that occupied important therapeutic niches, could be replaced. Reasons for the clinically relevant toxicity will be clarified and future substitutes for these drugs presented in this review.
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14
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Lawson K. Pharmacology and clinical applications of flupirtine: Current and future options. World J Pharmacol 2019; 8:1-13. [DOI: 10.5497/wjp.v8.i1.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/17/2018] [Accepted: 01/05/2019] [Indexed: 02/06/2023] Open
Abstract
Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently, this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets, including Kv7 channels, G-protein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets (e.g., Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications. Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit, especially in complex clinical conditions, requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.
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Affiliation(s)
- Kim Lawson
- Department of Biosciences and Chemistry, Biomolecular Sciences Research Centre, Sheffield Hallam University, Sheffield S1 1WB, United Kingdom
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15
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Surur AS, Bock C, Beirow K, Wurm K, Schulig L, Kindermann MK, Siegmund W, Bednarski PJ, Link A. Flupirtine and retigabine as templates for ligand-based drug design of KV7.2/3 activators. Org Biomol Chem 2019; 17:4512-4522. [DOI: 10.1039/c9ob00511k] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Puzzling stability: molecular jigsaw pieces of residues characterized in light of activity, lipophilicity, stability against oxidation, and hepatotoxicity were combined to yield flupirtine analogue 25b.
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Affiliation(s)
- Abdrrahman S. Surur
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Christian Bock
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Kristin Beirow
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Konrad Wurm
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Lukas Schulig
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Markus K. Kindermann
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Werner Siegmund
- Center of Drug Absorption and Transport (C_DAT) Greifswald
- Germany
| | - Patrick J. Bednarski
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
| | - Andreas Link
- Pharmaceutical and Medicinal Chemistry
- Institute of Pharmacy
- University of Greifswald
- 17487 Greifswald
- Germany
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16
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Patil MA, Matter BA, Raol YH, Bourne DWA, Kelley RA, Kompella UB. Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats. Pharmaceutics 2018; 10:E281. [PMID: 30558371 PMCID: PMC6320943 DOI: 10.3390/pharmaceutics10040281] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 02/07/2023] Open
Abstract
Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0⁻24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.
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Affiliation(s)
- Madhoosudan A Patil
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Brock A Matter
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Yogendra H Raol
- Department of Pediatrics, Division of Neurology, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - David W A Bourne
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Ryan A Kelley
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
| | - Uday B Kompella
- Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
- Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
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Konishi K, Fukami T, Ogiso T, Nakajima M. In vitro approach to elucidate the relevance of carboxylesterase 2 and N-acetyltransferase 2 to flupirtine-induced liver injury. Biochem Pharmacol 2018; 155:242-251. [PMID: 30028988 DOI: 10.1016/j.bcp.2018.07.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/14/2018] [Indexed: 12/30/2022]
Abstract
The use of flupirtine, an analgesic, has been restricted in European countries because it causes liver injury in rare cases. Flupirtine is primarily metabolized to D-13223, an acetylamino form. In the process of D-13223 formation, it has been hypothesized that a reactive metabolite is formed which may be involved in flupirtine hepatotoxicity. The purpose of this study was to identify the potential reactive metabolite and the responsible enzymes in the human liver to get a clue to the mechanism of hepatotoxicity. Using recombinant enzymes, we found that D-13223 was formed from flupirtine via hydrolysis by carboxylesterase 2 (CES2) and subsequent acetylation by N-acetyltransferase (NAT) 2. A conjugate of N-acetyl-l-cysteine (NAC), a nucleophile, was detected by incubation of flupirtine with CES2, and the conjugate formation in human liver microsomes was inhibited by CES2 inhibitors, indicating that a reactive metabolite, which may be a quinone diimine, was produced in the process of CES2-mediated hydrolysis of flupirtine. The formation of the NAC conjugate in liver S9 samples from NAT2 slow acetylators was significantly higher than that from NAT2 rapid/intermediate acetylators, indicating that NAT2 could function as a detoxification enzyme for flupirtine. CES2-overexpressing HepG2 cells showed remarkable lactate dehydrogenase leakage under flupirtine treatment, while no cytotoxicity was observed in control cells, suggesting that the reactive metabolite formed by CES2-mediated hydrolysis of flupirtine would be a trigger of hepatotoxicity. NAT2 slow acetylators with high CES2 activity could be highly susceptible to flupirtine-induced liver injury.
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Affiliation(s)
- Keigo Konishi
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tatsuki Fukami
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; WPI Nano Life Science Institute (WPI Nano-LSI), Kanazawa University, Kanazawa, Japan.
| | - Takuo Ogiso
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan
| | - Miki Nakajima
- Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan; WPI Nano Life Science Institute (WPI Nano-LSI), Kanazawa University, Kanazawa, Japan
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18
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Borlak J, van Bömmel F, Berg T. N-acetylcysteine and prednisolone treatment improved serum biochemistries in suspected flupirtine cases of severe idiosyncratic liver injury. Liver Int 2018; 38:365-376. [PMID: 28782153 DOI: 10.1111/liv.13538] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 07/29/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The analgesic flupirtine has been linked to cases of severe idiosyncratic drug-induced liver injury (sFILI). We therefore examined whether N-acetylcysteine (NAC) and glucocorticoid therapy is effective in the management of sFILI. METHODS In a retrospective cohort study efficacy of NAC-infusion and oral prednisolone treatments on liver-function-tests (LFTs) and clinical outcome of 21 sFILI cases was evaluated by comparing it to an external cohort of 30 sFILI cases not receiving the antidote. LFTs were also assayed in human hepatocyte cultures treated with flupirtine for 96 hours. Additionally, modulation of glutathione stores in cultures of human hepatocytes treated with 80 drugs was investigated. RESULTS Upon admission, patients presented Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin elevations of up to 90-, 35- and 30-fold of upper limits of normal (ULN) respectively. The average INR was 2.2, and 50% of patients had a high Model for end-stage liver disease (MELD) score of ≥25 and included 5 cases of 28-32. The combined NAC/prednisolone treatment was well tolerated and led to significant ALT, AST and INR improvements within 2 weeks. However, the hyperbilirubinaemia resolved slowly. Two patients with late start of NAC/prednisolone treatment developed hepatic encephalopathy and required liver transplantation; the remaining patients recovered without long-term sequela. Based on serum biochemistries sFILI cases resolved more rapidly (P < .01) when compared to untreated sFILI patients and included a case with fatal outcome. Additionally, in vitro studies revealed glutathione depletion as a common culprit for drugs with liver liabilities. CONCLUSIONS Based on these initial findings a prospective randomized clinical trial (RCT) is needed to confirm safety and efficacy of NAC/prednisolone treatment in sFILI.
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Affiliation(s)
- Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Florian van Bömmel
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
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Peta V, Tse C, Perazzo H, Munteanu M, Ngo Y, Ngo A, Ramanujam N, Verglas L, Mallet M, Ratziu V, Thabut D, Rudler M, Thibault V, Schuppe-Koistinen I, Bonnefont-Rousselot D, Hainque B, Imbert-Bismut F, Merz M, Kullak-Ublick G, Andrade R, van Boemmel F, Schott E, Poynard T. Serum apolipoprotein A1 and haptoglobin, in patients with suspected drug-induced liver injury (DILI) as biomarkers of recovery. PLoS One 2017; 12:e0189436. [PMID: 29287080 PMCID: PMC5747433 DOI: 10.1371/journal.pone.0189436] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 11/26/2017] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND There is a clear need for better biomarkers of drug-induced-liver-injury (DILI). AIMS We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI. METHODS We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN), and BILI <2x ULN. RESULTS After adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending) combining the ActiTest components without BILI and ALT (used as references), apolipoprotein-A1, haptoglobin, alpha-2-macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115) and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500). Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4-8 weeks and at 8-12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases. CONCLUSIONS We identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated.
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Affiliation(s)
| | - Chantal Tse
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Hugo Perazzo
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Mona Munteanu
- Department of Research, Biopredictive, Paris, France
| | - Yen Ngo
- Department of Research, Biopredictive, Paris, France
| | - An Ngo
- Department of Research, Biopredictive, Paris, France
| | - Nittia Ramanujam
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Lea Verglas
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Maxime Mallet
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Vlad Ratziu
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
- University Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale UMR 938, Paris, France
| | - Dominique Thabut
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
- University Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale UMR 938, Paris, France
| | - Marika Rudler
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Vincent Thibault
- Department of Virology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | | | - Dominique Bonnefont-Rousselot
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Bernard Hainque
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Françoise Imbert-Bismut
- Department of Biochemistry, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
| | - Michael Merz
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland
| | - Gerd Kullak-Ublick
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Mechanistic Safety, Novartis Global Drug Development, Basel, Switzerland
| | - Raul Andrade
- Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Málaga, Spain
| | - Florian van Boemmel
- Clinic for Hepatology and Rheumatology, Hepatology Section, University Hospital Leipzig, Leipzig, Germany
| | - Eckart Schott
- Clinic for Hepatology and Rheumatology, Hepatology Section, University Hospital Charité, Berlin, Germany
| | - Thierry Poynard
- Department of Hepatology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique Hopitaux de Paris, Paris, France
- University Pierre et Marie Curie, Institut National de la Santé et de la Recherche Médicale UMR 938, Paris, France
- * E-mail:
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Liu Y, Huo H, Zhao Z, Hu W, Sun Y, Tang Y. Bioequivalence study of two formulations of flupirtine maleate capsules in healthy male Chinese volunteers under fasting and fed conditions. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:3441-3448. [PMID: 29238169 PMCID: PMC5716300 DOI: 10.2147/dddt.s149913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aim This study developed a high-performance liquid chromatography–tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. Materials and methods There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC0−t), area under the plasma concentration–time curve from administration to infinite time (AUC0−∞), and Cmax were used for BE assessment. Results Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%–108.2%) for AUC0−t, 102.9% (98.2%–107.9%) for AUC0−∞, and 97.0% (85.9%–109.5%) for Cmax. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%–105.1%) for AUC0−t, 101.6% (98.5%–104.8%) for AUC0−∞, and 103.5% (94.7%–113.0%) for Cmax. The difference between test and reference formulations, Tmax, was not statistically significant. The 90% CIs of the test/reference AUC ratio and Cmax ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. Conclusion The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting.
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Affiliation(s)
- Yanfang Liu
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
| | - Hua Huo
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
| | - Zhibo Zhao
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
| | - Wenli Hu
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
| | - Yujia Sun
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
| | - Yunbiao Tang
- Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
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HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics 2016; 26:218-24. [PMID: 26959717 DOI: 10.1097/fpc.0000000000000209] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls. DILI was diagnosed by causality assessment and expert review. Human leucocyte antigen (HLA) and single nucleotide polymorphism genotypes were imputed from the GWAS data, with direct HLA typing performed on selected cases to validate HLA predictions. Four replication cases that were unavailable for the GWAS were genotyped by direct HLA typing, yielding an overall total of 10 flupirtine DILI cases. RESULTS In the six flupirtine DILI cases included in the GWAS, we found a significant enrichment of the DRB1*16:01-DQB1*05:02 haplotype compared with the controls (minor allele frequency cases 0.25 and minor allele frequency controls 0.013; P=1.4 × 10(-5)). We estimated an odds ratio for haplotype carriers of 18.7 (95% confidence interval 2.5-140.5, P=0.002) using population-specific HLA control data. The result was replicated in four additional cases, also with a haplotype frequency of 0.25. In the combined cohort (six GWAS plus four replication cases), the haplotype was also significant (odds ratio 18.7, 95% confidence interval 4.31-81.42, P=6.7 × 10(-5)). CONCLUSION We identified a novel HLA class II association for DILI, confirming the important contribution of HLA genotype towards the risk of DILI generally.
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22
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TAMH: A Useful In Vitro Model for Assessing Hepatotoxic Mechanisms. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4780872. [PMID: 28074186 PMCID: PMC5198153 DOI: 10.1155/2016/4780872] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 11/10/2016] [Accepted: 11/24/2016] [Indexed: 02/07/2023]
Abstract
In vitro models for hepatotoxicity can be useful tools to predict in vivo responses. In this review, we discuss the use of the transforming growth factor-α transgenic mouse hepatocyte (TAMH) cell line, which is an attractive model to study drug-induced liver injury due to its ability to retain a stable phenotype and express drug-metabolizing enzymes. Hepatotoxicity involves damage to the liver and is often associated with chemical exposure. Since the liver is a major site for drug metabolism, drug-induced liver injury is a serious health concern for certain agents. At the molecular level, various mechanisms may protect or harm the liver during drug-induced hepatocellular injury including signaling pathways and endogenous factors (e.g., Bcl-2, GSH, Nrf2, or MAPK). The interplay between these and other pathways in the hepatocyte can change upon drug or drug metabolite exposure leading to intracellular stress and eventually cell death and liver injury. This review focuses on mechanistic studies investigating drug-induced toxicity in the TAMH line and how alterations to hepatotoxic mechanisms in this model relate to the in vivo situation. The agents discussed herein include acetaminophen (APAP), tetrafluoroethylcysteine (TFEC), flutamide, PD0325901, lapatinib, and flupirtine.
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23
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Giorgi M, De Vito V, Poapolathep A, Rychshanova R, Sgorbini M, Owen H. Pharmacokinetics and disposition of flupirtine in the horse. Vet J 2015; 208:76-80. [PMID: 26681139 DOI: 10.1016/j.tvjl.2015.08.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 05/26/2015] [Accepted: 08/15/2015] [Indexed: 01/15/2023]
Abstract
Flupirtine (FLU) is a non-opioid analgesic drug, with no antipyretic or anti-inflammatory effects, used in the treatment of a wide range of pain states in human beings. It does not induce the side effects associated with the classical drugs used as pain relievers. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy horses. Six mixed breed adult mares were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square). Group 1 (n = 3) received a single dose of 1 mg/kg of FLU injected IV into the jugular vein. Group 2 (n = 3) received FLU (5 mg/kg) via nasogastric tube. The animals then swapped groups after a 1-week wash-out period and the doses were repeated. Blood samples (5 mL) were collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, 36 and 48 h and plasma was then analysed by a validated HPLC method. Some mild and transient adverse effects (that spontaneously resolved within 5 min) were observed in 2/6 animals after IV administration. No adverse effects were noticed in the PO administration group. After IV and PO administrations, FLU was detectable in plasma for up to 36 h. The mean elimination half-life was longer after PO (10.27 h) than after IV (3.02 h) administration. The oral bioavailability was 71.4 ± 33.1%. After compartmental simulation/modelling, an oral dose of 2.6 mg/kg was calculated to give Cmax and AUC values in horses similar to those reported in humans after a clinical dose administration with a theoretical FLU effective plasma concentration of 187 ng/mL. These findings may form the basis for further studies concerning this active ingredient in equine medicine.
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Affiliation(s)
- M Giorgi
- Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy.
| | - V De Vito
- Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy
| | - A Poapolathep
- Department of Veterinary Pharmacology, Faculty of Veterinary Medicine, University of Kasetsart, Bangkok, Thailand
| | - R Rychshanova
- Veterinary School, Kostanay State A. Baitursynov University, Kostanay, Kazakhstan
| | - M Sgorbini
- Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy
| | - H Owen
- School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton, Queensland 4343, Australia
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Siegmund W, Modess C, Scheuch E, Methling K, Keiser M, Nassif A, Rosskopf D, Bednarski PJ, Borlak J, Terhaag B. Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1. Br J Clin Pharmacol 2015; 79:501-13. [PMID: 25264565 PMCID: PMC4345960 DOI: 10.1111/bcp.12522] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 09/20/2014] [Indexed: 12/19/2022] Open
Abstract
AIMS The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. METHODS Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). RESULTS Flupirtine IR was rapidly but incompletely absorbed (∼ 72%). Repeated administration of flupirtine MR showed lower bioavailability (∼ 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2. CONCLUSIONS Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.
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Affiliation(s)
- Werner Siegmund
- Department of Clinical Pharmacology, University Medicine GreifswaldGreifswald, Germany
| | - Christiane Modess
- Department of Clinical Pharmacology, University Medicine GreifswaldGreifswald, Germany
| | - Eberhard Scheuch
- Department of Clinical Pharmacology, University Medicine GreifswaldGreifswald, Germany
| | - Karen Methling
- Department of Biochemistry, University of GreifswaldGreifswald, Germany
| | - Markus Keiser
- Department of Clinical Pharmacology, University Medicine GreifswaldGreifswald, Germany
| | - Ali Nassif
- Department of Clinical Pharmacology, University Medicine GreifswaldGreifswald, Germany
| | - Dieter Rosskopf
- Department of Pharmacology of the Center of Drug Absorption and Transport (C_DAT), University Medicine GreifswaldGreifswald, Germany
| | - Patrick J Bednarski
- Department of Pharmaceutical and Medicinal Chemistry, University of GreifswaldGreifswald, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical SchoolHannover, Germany
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Scheuch E, Methling K, Bednarski PJ, Oswald S, Siegmund W. Quantitative LC-MS/MS determination of flupirtine, its N-acetylated and two mercapturic acid derivatives in man. J Pharm Biomed Anal 2015; 102:377-85. [PMID: 25459937 DOI: 10.1016/j.jpba.2014.09.010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 08/29/2014] [Accepted: 09/09/2014] [Indexed: 11/23/2022]
Abstract
The non-opiate analgesic drug flupirtine was shown in vitro to undergo hydrolysis followed by N-acetylation to form D13223, glucuronidation and conjugation with glutathione to form the stable mercapturic acid derivatives M-424 and M-466. To quantify flupirtine and its metabolites in samples obtained in a clinical study in healthy subjects selected on their genotype of NAT2, UGT1A1 and GSTP1, two LC-MS/MS methods were developed. The validation range for flupirtine and D-13223 in serum was 0.5-500 ng/ml. For urine and feces, the validation ranges for flupirtine and D-13223 were 20-5000 ng/ml and 5.0-5000 ng/ml, respectively. M-424 and M-466 could be quantified in urine between 5.0 and 5000 ng/ml. Free flupirtine and D-13223 were separated from serum, urine and feces with liquid-liquid extraction. For flupirtine and D-13223, the chromatography was performed on a XTerra C18 column isocratically with a mobile phase consisting of ammonium formate buffer (pH 3.5mM) and acetonitrile (50:50; v/v), for M-466 and M-424 a Synergi(®) Fusion-RP column was used and a linear gradient method with water/HCOOH (pH 3) and acetonitrile. The mass spectrometer operated both with electro spray ionization in positive multiple reaction monitoring mode. The developed methods fulfilled the current FDA criteria on bioanalytical method validation for accuracy (error: -16.9 to 11.2%), precision (1.2-13.4%), recovery, stability and matrix effects over the observed analytical range. Thus, the methods were suitable to quantify flupirtine absorption and metabolic disposition in man after single intravenous and oral dosing (100mg) and repeated oral administration (400mg once daily).
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Affiliation(s)
- Eberhard Scheuch
- Department of Clinical Pharmacology (ES, WS) of the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany.
| | - Karen Methling
- Department of Pharmaceutical Chemistry (KM, PJB), University of Greifswald, Germany
| | - Patrick J Bednarski
- Department of Pharmaceutical Chemistry (KM, PJB), University of Greifswald, Germany
| | - Stefan Oswald
- Department of Clinical Pharmacology (ES, WS) of the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
| | - Werner Siegmund
- Department of Clinical Pharmacology (ES, WS) of the Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany
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26
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Lemmerhirt CJ, Rombach M, Bodtke A, Bednarski PJ, Link A. Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV 7 channel opening activity but not hepatocyte toxicity. ChemMedChem 2014; 10:368-79. [PMID: 25392984 DOI: 10.1002/cmdc.201402442] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Indexed: 12/30/2022]
Abstract
Openers of neuronal voltage-gated potassium channels (KV ) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone diimines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV 7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.
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Affiliation(s)
- Christian J Lemmerhirt
- Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Ernst Moritz Arndt University, Friedrich-Ludwig-Jahn-Str. 17, 17487 Greifswald (Germany)
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De Vito V, Lebkowska-Wieruszewska B, Owen H, Kowalski CJ, Giorgi M. Pharmacokinetic profiles of the analgesic drug flupirtine in cats. Vet J 2014; 202:309-13. [PMID: 25011711 DOI: 10.1016/j.tvjl.2014.06.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 05/15/2014] [Accepted: 06/13/2014] [Indexed: 12/16/2022]
Abstract
Flupirtine (FLU) is a non-opioid analgesic drug with no antipyretic or antiphlogistic effects, used in the treatment of a wide range of pain states in human beings. There is a substantial body of evidence on the efficacy of FLU in humans but this is inadequate to recommend its off-label use in veterinary clinical practice. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy cats. Six mixed breed adult cats were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square). Group 1 (n = 3) received a single dose of 5 mg/kg of FLU injected IV into the jugular vein. Group 2 (n = 3) received the same dose via PO route. The wash out period was 1 week. Blood samples (1 mL) were collected at assigned times and plasma was then analysed by a validated HPLC method. No adverse effects at the point of injection and no behavioural changes or alterations in health parameters were observed in the animals during or after the study (up to 7 days after the full study). After IV administration, FLU was detectable in plasma up to 36 h. After PO administration, FLU plasma concentrations were lower than those following IV administration, but they were detectable over the same time range. The terminal part of both mean pharmacokinetic curves showed a similar trend of elimination. The oral bioavailability was approximately 40%. This is the first study of FLU in an animal species of veterinary interest and it could pave the way for the use of this active ingredient in the veterinary field.
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Affiliation(s)
- V De Vito
- Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy
| | | | - H Owen
- School of Veterinary Science, The University of Queensland, Gatton Campus, Gatton, Queensland 4343, Australia
| | - C J Kowalski
- Department of Pharmacology, University of Life Sciences, Akademicka 13, 20-950 Lublin, Poland
| | - M Giorgi
- Department of Veterinary Sciences, University of Pisa, Via Livornese (lato monte), San Piero a Grado, Italy.
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Douša M, Srbek J, Rádl S, Cerný J, Klecán O, Havlíček J, Tkadlecová M, Pekárek T, Gibala P, Nováková L. Identification, characterization, synthesis and HPLC quantification of new process-related impurities and degradation products in retigabine. J Pharm Biomed Anal 2014; 94:71-6. [PMID: 24552644 DOI: 10.1016/j.jpba.2014.01.042] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 01/23/2014] [Accepted: 01/26/2014] [Indexed: 01/07/2023]
Abstract
Two new impurities were described and determined using gradient HPLC method with UV detection in retigabine (RET). Using LC-HRMS, NMR and IR analysis the impurities were identified as RET-dimer I: diethyl {4,4'-diamino-6,6'-bis[(4-fluorobenzyl)amino]biphenyl-3,3'-diyl}biscarbamate and RET-dimer II: ethyl {2-amino-5-[{2-amino-4-[(4-fluorobenzyl) amino] phenyl} (ethoxycarbonyl) amino]-4-[(4-fluorobenzyl)amino] phenyl}carbamate. Reference standards of these impurities were synthesized followed by semipreparative HPLC purification. The mechanism of the formation of these impurities is also discussed. An HPLC method was optimized in order to separate, selectively detect and quantify all process-related impurities and degradation products of RET. The presented method, which was validated in terms of linearity, limit of detection (LOD), limit of quantification (LOQ) and selectivity is very quick (less than 11min including re-equilibration time) and therefore highly suitable for routine analysis of RET related substances as well as stability studies.
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Affiliation(s)
- Michal Douša
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic.
| | - Jan Srbek
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Stanislav Rádl
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Josef Cerný
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Ondřej Klecán
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Jaroslav Havlíček
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | | | - Tomáš Pekárek
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Petr Gibala
- Zentiva, k.s. Praha, U Kabelovny 130, 102 37 Praha 10, Czech Republic
| | - Lucie Nováková
- Department of Analytical Chemistry, Charles University, Faculty of Pharmacy, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
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Abstract
Flupirtine is neither an opioid nor a non steroidal anti-inflammatory drug (NSAID) producing its analgesic action through blockade of glutamate N-methyl-D-aspartate receptor. It is devoid of adverse effects of routinely used analgesic drugs, but is equally efficacious in reducing pain sensation. It has a distinctive mechanism of action, exerting a dual therapeutic effect with both analgesic and muscle relaxant properties that has utility in the treatment of pain, including that associated with muscle tension.
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Affiliation(s)
- S Harish
- Department of Pharmacology, Sri Devaraj Urs Medical College, Tamaka, Kolar, Karnataka, India
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Uberall MA, Mueller-Schwefe GHH, Terhaag B. Efficacy and safety of flupirtine modified release for the management of moderate to severe chronic low back pain: results of SUPREME, a prospective randomized, double-blind, placebo- and active-controlled parallel-group phase IV study. Curr Med Res Opin 2012; 28:1617-34. [PMID: 22970658 DOI: 10.1185/03007995.2012.726216] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To demonstrate non-inferior/superior efficacy of flupirtine modified release (MR) compared with tramadol/placebo for the management of moderate to severe chronic low back pain (LBP). RESEARCH DESIGN Randomized, double-blind, active-/placebo-controlled double-dummy multicenter study, performed in 31 German study centers. LBP patients (n = 363) with moderate pain intensity were randomized 1:1:1 to receive flupirtine MR 400 mg, tramadol extended release (ER) 200 mg, or matching placebo (each given OD in the evening) over 4 weeks. CLINICAL TRIAL REGISTRATION EudraCT 2009-013268-38. MAIN OUTCOME MEASURES Primary endpoint was change from baseline in the LBP intensity index (LBPIX; 11-point NRS) at week 4; last observation carried forward was used to impute missing scores. RESULTS Least square (LS) mean ± SD LBPIX changes from baseline at week 4 were clinically significant for all three treatment groups of the intent-to-treat (ITT) and the per-protocol (PP) population (n = 326/276): placebo (n = 110/96): -1.81 ± 1.65/-1.77 ± 1.59; flupirtine MR (n = 109/95): -2.23 ± 1.73/-2.28 ± 1.68; and tramadol ER (n = 107/85): -1.92 ± 1.84/2.03 ± 1.83 (p < 0.001 for each). ITT/PP treatment effects for flupirtine MR were non-inferior when compared with tramadol ER and superior when compared with placebo (p = 0.003/0.033). Significantly more ITT patients treated with flupirtine MR (59.6/37.6 showed a ≥30/50% LBPIX relief in comparison to placebo (46.4/24.6%; p vs. flupirtine MR: 0.049/0.037). Treatment contrasts for tramadol failed to reach significance vs. placebo. Within the safety population (n = 355), flupirtine MR (n = 119) was associated with a significantly lower incidence of treatment emergent AEs (TEAEs; 21.0%) and TEAE-related study discontinuations (3.4%) than tramadol ER (n = 116; 34.5/12.0%; p = 0.039/0.017) and exhibited an overall safety/tolerability profile non-inferior to placebo (n = 120; 15.8/3.3%; p = ns for each). Major limitations of this study were the short treatment duration, the comparison of different drug classes and the lack of a titration phase. CONCLUSIONS The analgesic efficacy of flupirtine MR 400 mg OD was comparable to that of tramadol ER 200 mg OD and superior to that of placebo.
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Affiliation(s)
- Michael A Uberall
- Institute for Neurological Sciences, Algesiology and Pediatrics, Nuernberg, Germany.
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31
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Hansen FK, Geffken D. Efficient synthesis of flupirtine analogues derived from pyrimidine. J Heterocycl Chem 2011. [DOI: 10.1002/jhet.725] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Anderson N, Borlak J. Correlation versus causation? Pharmacovigilance of the analgesic flupirtine exemplifies the need for refined spontaneous ADR reporting. PLoS One 2011; 6:e25221. [PMID: 22022383 PMCID: PMC3191146 DOI: 10.1371/journal.pone.0025221] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Accepted: 08/29/2011] [Indexed: 12/20/2022] Open
Abstract
Annually, adverse drug reactions result in more than 2,000,000 hospitalizations and rank among the top 10 causes of death in the United States. Consequently, there is a need to continuously monitor and to improve the safety assessment of marketed drugs. Nonetheless, pharmacovigilance practice frequently lacks causality assessment. Here, we report the case of flupirtine, a centrally acting non-opioid analgesic. We re-evaluated the plausibility and causality of 226 unselected, spontaneously reported hepatobiliary adverse drug reactions according to the adapted Bradford-Hill criteria, CIOMS score and WHO-UMC scales. Thorough re-evaluation showed that only about 20% of the reported cases were probable or likely for flupirtine treatment, suggesting an incidence of flupirtine-related liver injury of 1∶ 100,000 when estimated prescription data are considered, or 0.8 in 10,000 on the basis of all 226 reported adverse drug reactions. Neither daily or cumulative dose nor duration of treatment correlated with markers of liver injury. In the majority of cases (151/226), an average of 3 co-medications with drugs known for their liver liability was observed that may well be causative for adverse drug reactions, but were reported under a suspected flupirtine ADR. Our study highlights the need to improve the quality and standards of ADR reporting. This should be done with utmost care taking into account contributing factors such as concomitant medications including over-the-counter drugs, the medical history and current health conditions, in order to avoid unjustified flagging and drug warnings that may erroneously cause uncertainty among healthcare professionals and patients, and may eventually lead to unjustified safety signals of useful drugs with a reasonable risk to benefit ratio.
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Affiliation(s)
- Nora Anderson
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Juergen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
- Department of Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany
- * E-mail:
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Abstract
Flupirtine is a centrally acting, non-opioid analgesic that is available in a number of European countries for the treatment of a variety of pain states. The therapeutic benefits seen with flupirtine relate to its unique pharmacological properties. Flupirtine displays indirect NDMA receptor antagonism via activation of potassium channels and is the first representative of a pharmacological class denoted the 'selective neuronal potassium channel openers'. The generation of the M-current is facilitated by flupirtine via the opening of neuronal Kv7 potassium channels. The opening of these channels inhibits exaggerated neuronal action potential generation and controls neuronal excitability. Neuronal hyperexcitability is a physiological component of many pain states such as chronic pain, migraine and neurogenic pain. Although large-scale clinical trials are lacking, the clinical trial database available to date from smaller-scale studies, together with extensive clinical experience, indicate that flupirtine effectively reduces chronic musculoskeletal pain, migraine and neuralgias, amongst other types of pain. In addition, flupirtine produces, at recommended clinical doses, muscle-relaxing effects in the presence of abnormally increased muscle tension. Its analgesic and muscle-relaxant properties were comparable to tramadol and chlormezanone, respectively, in two prospective trials in patients with lower back pain. Cytoprotective, anti-apoptotic and antioxidant properties have also been associated with flupirtine use in a small number of studies to date. When provided as combination therapy with morphine, flupirtine increases the antinociceptive activity of morphine 4-fold. Flupirtine displays superior tolerability when compared with tramadol and pentazocine. The most common adverse effects associated with flupirtine use are drowsiness, dizziness, heartburn, dry mouth, fatigue and nausea. With respect to its molecular structure, mechanism of action and adverse event profile, flupirtine is a unique drug. Flupirtine is an analgesic with many potential therapeutic benefits that may prove useful in the treatment of many disease states.
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Affiliation(s)
- Jacques Devulder
- Department of Anaesthesia, Section Pain Clinic, Ghent University Hospital, Ghent, Belgium.
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34
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Klawe C, Maschke M. Flupirtine: pharmacology and clinical applications of a nonopioid analgesic and potentially neuroprotective compound. Expert Opin Pharmacother 2009; 10:1495-500. [DOI: 10.1517/14656560902988528] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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