Cytochrome P450 Specificity of Metabolism and Interactions of Oxybutynin in Human Liver Microsomes
Autor: | O. Pelkonen, E. Lukkari, P Taavitsainen, A Juhakoski |
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Rok vydání: | 1998 |
Předmět: |
Antifungal Agents
CYP3A Health Toxicology and Mutagenesis Pharmacology Hydroxylation Toxicology 030226 pharmacology & pharmacy Substrate Specificity 03 medical and health sciences 0302 clinical medicine Cytochrome P-450 Enzyme System Cytochrome P-450 CYP3A medicine Humans Drug Interactions Testosterone Oxybutynin Active metabolite biology CYP3A4 Chemistry Cytochrome P450 Oxidoreductases N-Demethylating 3. Good health Isoenzymes Ketoconazole 030220 oncology & carcinogenesis Microsomes Liver biology.protein Microsome Mandelic Acids Aryl Hydrocarbon Hydroxylases Itraconazole medicine.drug |
Zdroj: | Pharmacology & Toxicology. 82:161-166 |
ISSN: | 1600-0773 0901-9928 |
DOI: | 10.1111/j.1600-0773.1998.tb01418.x |
Popis: | Oxybutynin has an extensive first pass metabolism after oral administration, the main active metabolite being N-desethyloxybutynin. The purpose of this study was to investigate the CYP isoform specificity of oxybutynin N-deethylation and possible interactions. Oxybutynin N-deethylation in human liver microsomes in vitro was potently inhibited by ketoconazole (IC50 4.5 microM), less and variably by itraconazole and not by quinidine or several other reference inhibitors, suggesting that CYP3A enzymes are predominant catalysts of the reaction. Recombinant CYP3A5 enzyme had higher activity in oxybutynin N-deethylation than recombinant CYP3A4. Ketoconazole inhibited oxybutynin N-deethylation by the recombinant CYP3A4 and CYP3A5 almost completely, whereas itraconazole inhibited the activity of CYP3A4 more potently than that of CYP3A5. Oxybutynin inhibited CYP3A4- and CYP2D6- associated activities (testosterone 6 beta-hydroxylase and dextromethorphan O- demethylase, respectively) in human liver microsomes. CYP1A1/2-, CYP2A6-, CYP2C9- and CYP2E1-associated activities were inhibited less potently or not at all by oxybutynin when compared with reference inhibitors. Although the reasons for the weak and variable inhibition by itraconazole remain to be studied, it seems that oxybutynin is predominantly metabolized by CYP3A4 and CYP3A5 but not by CYP2D6. However, it seems to have some affinity also to the latter enzyme. |
Databáze: | OpenAIRE |
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