In vitro identification of metabolic pathways and cytochrome P450 enzymes involved in the metabolism of etoperidone
| Autor: | William J. Jones, Zhengyin Yan, Gary W. Caldwell, Bryan M. Rafferty, L. A. McKown, John A. Masucci, Wu-Nan Wu |
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| Rok vydání: | 2002 |
| Předmět: |
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Complementary Health Toxicology and Mutagenesis Biology Toxicology Biochemistry Mass Spectrometry Hydroxylation chemistry.chemical_compound Cytochrome P-450 Enzyme System medicine Humans Protein Isoforms Pharmacology chemistry.chemical_classification CYP3A4 Dose-Response Relationship Drug Cytochrome P450 General Medicine Metabolism Recombinant Proteins Metabolic pathway Kinetics Enzyme chemistry Liver Models Chemical Etoperidone Trazodone Steroid Hydroxylases biology.protein Microsome Microsomes Liver medicine.drug Chromatography Liquid |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 32(11) |
| ISSN: | 0049-8254 |
| Popis: | 1. In vitro studies have been carried out to investigate the metabolic pathways and identify the hepatic cytochrome P450 (CYP) enzymes involved in etoperidone (Et) metabolism. 2. Ten in vitro metabolites were profiled, quantified and tentatively identified after incubation with human hepatic S9 fractions. Et was metabolized via three metabolic pathways: (A) alkyl hydroxylation to form OH-ethyl-Et (M1); (B) phenyl hydroxylation to form OH-phenyl-Et (M2); and (C) N-dealkylation to form 1-m-chlorophenylpiperazine (mCPP, M8) and triazole propyl aldehyde (M6). Six additional metabolites were formed by further metabolism of M1, M2, M6 and M8. 3. Kinetic studies revealed that all metabolic pathways were monophasic, and the pathway leading to the formation of OH-ethyl-Et was the most efficient at eliminating the drug. On incubation with microsomes expressing individual recombinant CYPs, formation rates of M1-3 and M8 were 10-100-fold greater for CYP3A4 than that for other CYP forms. The formation of these metabolites was markedly inhibited by the CYP3A4-specific inhibitor ketoconazole, whereas other CYP-specific inhibitors did not show significant effects. In addition, the production of M1-3 and M8 was strongly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activities in 13 different human liver microsome samples. 4. Dealkylation of the major metabolite M1 to form mCPP (M8) was also investigated using microsomes containing recombinant CYP enzymes. The rate of conversion of M1 to mCPP by CYP3A4 was 503.0 +/- 3.1 pmole nmole(-1) min(-1). Metabolism of M1 to M8 by other CYP enzymes was insignificant. In addition, this metabolism in human liver microsomes was extensively inhibited by the CYP3A4 inhibitor ketoconazole, but not by other CYP-specific inhibitors. In addition, conversion of M1 to M8 was highly correlated with CYP3A4-mediated testosterone 6beta-hydroxylase activity. 5. The results strongly suggest that CYP3A4 is the predominant enzyme-metabolizing Et in humans. |
| Databáze: | OpenAIRE |
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