Conflicting alterations in hepatic expression of CYP3A and enzyme kinetics in rats exposed to 5-fluorouracil: relevance to pharmacokinetics of midazolam
Autor: | Katsuhito Nagai, Yuya Sasaki, Shuhei Fukuno, Hiroki Konishi, Mai Fujiike |
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Rok vydání: | 2019 |
Předmět: |
Male
Pyrimidine CYP3A Midazolam Health Toxicology and Mutagenesis Pharmacology Hydroxylation Toxicology 030226 pharmacology & pharmacy Biochemistry Protein expression Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics medicine Animals Cytochrome P-450 CYP3A Enzyme kinetics Body Weight Cancer Organ Size General Medicine medicine.disease Kinetics Liver chemistry Fluorouracil 030220 oncology & carcinogenesis Inactivation Metabolic Microsomes Liver Cytochrome P-450 CYP3A Inhibitors Administration Intravenous medicine.drug |
Zdroj: | Xenobiotica. 49:1470-1477 |
ISSN: | 1366-5928 0049-8254 |
Popis: | 1. 5-Fluorouracil (5-FU) is a pyrimidine derivative widely used for the treatment of cancer. In this study, we investigated the effects of 5-FU on the protein expression of hepatic CYP3A and their enzyme activity for metabolizing midazolam (MDZ), a typical substrate of CYP3A, in rat liver microsomes. We also examined the pharmacokinetic behavior of intravenously administered MDZ in rats treated with 5-FU (120 mg/kg, ip). 2. 5-FU was shown to induce hepatic CYP3A2 protein 2 days after administration without changing the expression of CYP3A1/3A23. However, affinity of 5-FU-inducible CYP3A protein to MDZ for its 4- and 1'-hydroxylation was decreased. Furthermore, the susceptibility of MDZ hydroxylation activity to a CYP3A inhibitor differed between the control and 5-FU groups. 3. Pharmacokinetic analysis of the MDZ disposition demonstrated no significant differences in the total clearance (CL |
Databáze: | OpenAIRE |
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