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Croconazole metabolism in rats
M Nakano1, M Takeuchi, S Kawahara
1Shionogi & Co. Ltd, Shionogi Research Laboratories, Osaka, Japan.
Summary
This study identified four key metabolites of croconazole in rats, revealing differences in drug elimination and excretion between males and females. These findings are crucial for understanding croconazole
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Medicinal Chemistry
- Toxicology
Background:
- Croconazole is an imidazole antifungal agent.
- Understanding its metabolic fate and excretion is essential for assessing its efficacy and safety.
Purpose of the Study:
- To identify and characterize the metabolites of croconazole in rats.
- To investigate the pharmacokinetic differences in croconazole elimination between male and female rats.
- To quantify the excretion patterns of identified metabolites in urine and bile.
Main Methods:
- Subcutaneous administration of croconazole to male and female rats.
- Identification of metabolites using mass spectrometry, NMR, GLC, and TLC.
- Analysis of drug and metabolite levels in plasma, urine, and bile.
Main Results:
- Four major metabolites were identified: o-hydroxyacetophenone sulphate (M1S), 1-(1-(2-hydroxyphenacyl)vinyl)-1H-imidazole sulphate (M12S), 2-(3-chlorobenzyloxy)phenacyl alcohol (M2), and 2-(3-chlorobenzyloxy)benzoic acid (M9-1).
- Croconazole elimination from plasma was faster in male rats than in female rats.
- Significant sex-based differences were observed in the urinary and biliary excretion percentages of M12S, M1S, M2, and M9-1.
Conclusions:
- Croconazole undergoes extensive metabolism in rats, producing distinct metabolites.
- Sex-dependent pharmacokinetic differences in croconazole elimination and metabolite excretion exist in rats.
- These findings provide valuable insights into the metabolic profile and disposition of croconazole.