In vitro metabolism of the new antifungal dapaconazole using liver microsomes.

Autor: Antunes NJ; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address: nataliciaja@gmail.com., Coombes G; Analytical Services International (ASI) Ltd., St George's - University of London, Cranmer Terrace, London, SW17 0RE, UK., da Cunha KF; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil; Campinas Poison Control Center, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil., Moreira FL; Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil., Pilon AC; NPPNS, Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, São Paulo, Brazil., Lopes NP; NPPNS, Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, São Paulo, Brazil., Costa JLD; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil; Campinas Poison Control Center, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil., Kipper K; Institute of Chemistry, University of Tartu, 14a Ravila Street, 50411, Tartu, Estonia., Couchman L; Analytical Services International (ASI) Ltd., St George's - University of London, Cranmer Terrace, London, SW17 0RE, UK; Pharmaceutical Sciences Clinical Academic Group, King's College London, London, United Kingdom., Johnston A; Analytical Services International (ASI) Ltd., St George's - University of London, Cranmer Terrace, London, SW17 0RE, UK; Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom., De Nucci G; Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil; Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil.
Jazyk: angličtina
Zdroj: Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2022 Dec; Vol. 47, pp. 100475. Date of Electronic Publication: 2022 Sep 20.
DOI: 10.1016/j.dmpk.2022.100475
Abstrakt: Dapaconazole is a new antifungal imidazole that has been shown a high efficacy against several pathogenic fungi. This study aimed to investigate the interspecies variation in the in vitro metabolic profiles and in vivo hepatic clearance (CL H,in vivo ) prediction of dapaconazole using liver microsomes from male Sprague Dawley rat, male Beagle dog and mixed gender human using a liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method. In addition, the produced metabolites were identified by ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS/MS). The microsomal protein concentration of 0.1 mg/mL and the incubation time of 10 min were employed for the kinetics determination, resulting in a sigmoidal kinetic profile for all species evaluated. The predicted CL H,in vivo was 6.5, 11.6 and 7.5 mL/min/kg for human, rat and dog, respectively. Furthermore, five metabolized products were identified. These findings provide preliminary information for understanding dapaconazole metabolism and the interspecies differences in catalytic behaviours, supporting the choice of a suitable laboratory animal for future pharmacokinetics and metabolism studies.
Competing Interests: Declaration of competing interest The authors declare no conflicts of interest.
(Copyright © 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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