Effects of aging and rifampicin pretreatment on the pharmacokinetics of human cytochrome P450 probes caffeine, warfarin, omeprazole, metoprolol and midazolam in common marmosets genotyped for cytochrome P450 2C19
| Autor: | Masayuki Mogi, Shotaro Uehara, Takashi Kusama, Yasuhiro Uno, Makiko Shimizu, Akiko Toda, Erika Sasaki, Hiroshi Yamazaki, Takashi Inoue, Masahiro Utoh |
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| Rok vydání: | 2017 |
| Předmět: |
Male
Aging Genotype Health Toxicology and Mutagenesis Midazolam CYP2C19 Pharmacology Toxicology 030226 pharmacology & pharmacy Biochemistry Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics Caffeine medicine Animals Humans heterocyclic compounds Omeprazole Metoprolol Warfarin Callithrix General Medicine Cytochrome P-450 CYP2C19 chemistry 030220 oncology & carcinogenesis Administration Intravenous Rifampin Rifampicin medicine.drug |
| Zdroj: | Xenobiotica; the fate of foreign compounds in biological systems. 48(7) |
| ISSN: | 1366-5928 |
| Popis: | 1. The pharmacokinetics were investigated for human cytochrome P450 probes after single intravenous and oral administrations of 0.20 and 1.0 mg/kg, respectively, of caffeine, warfarin, omeprazole, metoprolol and midazolam to aged (10-14 years old, n = 4) or rifampicin-treated/young (3 years old, n = 3) male common marmosets all genotyped as heterozygous for a cytochrome P450 2C19 variant. 2. Slopes of the plasma concentration-time curves after intravenous administration of warfarin and midazolam were slightly, but significantly (two-way analysis of variance), decreased in aged marmosets compared with young marmosets. The mean hepatic clearances determined by in silico fitting for individual pharmacokinetic models of warfarin and midazolam in the aged group were, respectively, 23% and 56% smaller than those for the young group. 3. Significantly enhanced plasma clearances of caffeine, warfarin, omeprazole and midazolam were evident in young marmosets pretreated with rifampicin (25 mg/kg daily for 4 days). Two- to three-fold increases in hepatic intrinsic clearance values were observed in the individual pharmacokinetic models. 4. The in vivo dispositions of multiple simultaneously administered drugs in old, young and P450-enzyme-induced marmosets were elucidated. The results suggest that common marmosets could be experimental models for aged, induced or polymorphic P450 enzymes in P450-dependent drug metabolism studies. |
| Databáze: | OpenAIRE |
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