In vitro metabolism of the new antifungal dapaconazole using liver microsomes

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Antunes, Natalicia de Jesus ; Coombes, Gemma ; da Cunha, Kelly Francisco ; Moreira, Fernanda de Lima ; Pilon, Alan C. ; Lopes, Norberto Peporine ; da Costa, Jose Luiz ; Kipper, Karin ; Couchman, Lewis ; Johnston, Atholl ; De Nucci, Gilberto

• Document type: Journal article
• Source: DRUG METABOLISM AND PHARMACOKINETICS; v. 47, p. 10-pg., 2022-11-09.

Abstract

Dapaconazole is a new antifungal imidazole that has been shown a high efficacy against several path-ogenic fungi. This study aimed to investigate the interspecies variation in the in vitro metabolic profiles and in vivo hepatic clearance (CLH,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 in-cubation time of 10 min were employed for the kinetics determination, resulting in a sigmoidal kinetic profile for all species evaluated. The predicted CLH,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.(c) 2022 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved. (AU)

• FAPESP's process: 19/16805-4 - Evaluation of the pathophysiological role of endothelial catecholamines
• Grantee: Gilberto de Nucci
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/22506-1 - Metabolism of dapaconazole
• Grantee: Natalícia de Jesus Antunes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral