Role of cytochrome P450 enzymes in fimasartan metabolism in vitro
| Autor: | Chang Seon Ryu, Ji-Yoon Lee, Soo Heui Paik, Yong Ha Chi, Young Jae Choi, Sang Kyum Kim |
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| Rok vydání: | 2018 |
| Předmět: |
Tetrazoles
In Vitro Techniques Hydroxylation Toxicology 030226 pharmacology & pharmacy Angiotensin Receptor Antagonists 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cytochrome P-450 Enzyme System Tandem Mass Spectrometry medicine Humans Fimasartan Enzyme kinetics reproductive and urinary physiology chemistry.chemical_classification CYP3A4 biology Biphenyl Compounds Cytochrome P450 hemic and immune systems General Medicine Metabolism Monooxygenase Recombinant Proteins biological factors Kinetics Pyrimidines Enzyme chemistry Biochemistry 030220 oncology & carcinogenesis embryonic structures Oxygenases biology.protein Thermodynamics Oxidation-Reduction Chromatography Liquid Food Science medicine.drug |
| Zdroj: | Food and Chemical Toxicology. 115:375-384 |
| ISSN: | 0278-6915 |
| DOI: | 10.1016/j.fct.2018.03.036 |
| Popis: | Fimasartan (FMS), an angiotensin II receptor antagonist, is metabolized to FMS S-oxide, FMS N-glucuronide, oxidative desulfurized FMS (BR-A-557), and hydroxy-n-butyl FMSs. The purpose of this study was to characterize enzymes involved in NADPH-dependent FMS metabolism using recombinant enzymes such as cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), as well as selective chemical inhibitors. The results showed that CYP, but not FMO, plays a major role in FMS metabolism. CYP2C9, CYP3A4, and CYP3A5 were involved in the formation of FMS S-oxide, which was further metabolized to BR-A-557 by CYP3A4/5. CYP2C9 played an exclusive role in n-butyl hydroxylation. The specificity constant (kcat/Km) values for S-oxidation by CYP2C9, CYP3A4, and CYP3A5 were 0.21, 0.34, and 0.19 μM-1∙min-1, respectively. The kcat/Km values of hydroxylation at the 1-, 2-/3-, and 4-n-butyl group in CYP2C9 were 0.0076, 0.041, and 0.035 μM-1∙min-1, respectively. The kcat and Km values provide information for the prediction of FMS metabolism in vivo. In addition, simultaneous determination of the FMS metabolites may be used to evaluate CYP2C9 and CYP3A4/5 activity. |
| Databáze: | OpenAIRE |
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