In vitroinhibition and enhancement of liver microsomal S-777469 metabolism by long-chain fatty acids and serum albumin: insight intoin vitroandin vivodiscrepancy of metabolite formation in humans
| Autor: | Norie Murayama, Takushi Kanazu, Yoshitaka Yamaguchi, Hiroshi Yamazaki, Kazutaka Sekiguchi |
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| Rok vydání: | 2015 |
| Předmět: |
Pyridones
Health Toxicology and Mutagenesis Metabolite Carboxylic acid Serum albumin Myristic acid Toxicology 030226 pharmacology & pharmacy Biochemistry Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Animals Humans CYP2C9 Cytochrome P-450 CYP2C9 Pharmacology chemistry.chemical_classification biology Fatty Acids Fatty acid Serum Albumin Bovine General Medicine Recombinant Proteins Kinetics Oleic acid Phenotype chemistry 030220 oncology & carcinogenesis Metabolome Microsomes Liver biology.protein Cattle Arachidonic acid Oxidation-Reduction |
| Zdroj: | Xenobiotica. 46:495-502 |
| ISSN: | 1366-5928 0049-8254 |
| Popis: | 1. It was previously demonstrated that 10% of S-777469, a cannabinoid receptor 2 selective agonist, is metabolized to its carboxylic acid metabolite (S-777469 5-carboxylic acid, 5-CA) in humans in vivo, while the formation of 5-CA is extremely low in human cryopreserved hepatocytes and liver microsomes (HLMs). In this study, factors causing the different metabolite formation rates of S-777469 in vitro and in vivo were investigated. 2. Formation of 5-CA and S-777469 5-hydroxymethyl (5-HM), a precursor metabolite of 5-CA, was catalyzed by CYP2C9. Arachidonic acid, α-linolenic acid, oleic acid and myristic acid, which have been reported to exist in liver microsomes, inhibited S-777469 oxidation by CYP2C9, but serum albumin enhanced this reactions. 3. The IC50 values of these fatty acids for 5-CA formation from 5-HM were lower than those of 5-HM formation from S-777469. Serum albumin extensively enhanced 5-CA formation from 5-HM in comparison to 5-HM formation from S-777469. 4. CYP2C9 was the enzyme responsible for S-777469 oxidation in human livers. The suppressive effects of several fatty acids and enhancing action of serum albumin in vitro are likely to be the causal factors for the apparently different rates of in vitro and in vivo metabolite formation of S-777469. |
| Databáze: | OpenAIRE |
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