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In vitro metabolism of the new antifungal dapaconazole using liver microsomes

Natalícia de Jesus Antunes1, Gemma Coombes2, Kelly Francisco da Cunha3

  • 1Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil.

Drug Metabolism and Pharmacokinetics
|November 12, 2022
PubMed

Insights

This study investigated dapaconazole metabolism across species, predicting hepatic clearance (CLH,in vivo) and identifying metabolites. Findings reveal interspecies differences, aiding future pharmacokinetic studies.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Toxicology

Background:

  • Dapaconazole is a novel imidazole antifungal with demonstrated efficacy against pathogenic fungi.
  • Understanding drug metabolism and clearance is crucial for predicting in vivo pharmacokinetics and ensuring drug safety.

Purpose of the Study:

  • To investigate interspecies variations in the in vitro metabolic profiles of dapaconazole.
  • To predict the in vivo hepatic clearance (CLH,in vivo) of dapaconazole in rats, dogs, and humans.
  • To identify the metabolites of dapaconazole produced in liver microsomes.

Main Methods:

  • Utilized ultra-high-performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) for metabolic profiling.
  • Employed liver microsomes from male Sprague Dawley rat, male Beagle dog, and mixed-gender human subjects.
  • Identified metabolites using ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS).

Main Results:

  • A sigmoidal kinetic profile was observed for dapaconazole metabolism in all evaluated species.
  • Predicted in vivo hepatic clearance (CLH,in vivo) values were 6.5 mL/min/kg for humans, 11.6 mL/min/kg for rats, and 7.5 mL/min/kg for dogs.
  • Five distinct dapaconazole metabolites were identified.

Conclusions:

  • Significant interspecies differences exist in dapaconazole's metabolic profiles and hepatic clearance.
  • These findings provide essential preliminary data for understanding dapaconazole metabolism.
  • The study supports the selection of appropriate animal models for future pharmacokinetic and metabolism investigations.
Keywords:
Cytochrome P450DapaconazoleIn vitro metabolismLC-MS/MSMicrosomes

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