Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil |
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| Authors: | Shuhei Fukuno Keita Kasahara Yuki Mizobata Sachiko Omotani Yasutoshi Hatsuda |
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| Affiliation: | 1. Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan and;2. Laboratory of Practical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi, Japan |
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| Abstract: | 1.?We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats.2.?Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss).3.?The metabolic production of 4-hydroxylated TB in hepatic microsomes was significantly reduced by the administration of 5-FU.4.?The expression level of mRNAs for hepatic CYP2C6 and CYP2C11 was significantly lower than in the control group when the rats were pretreated with 5-FU.5.?These results demonstrated that the pharmacokinetic profile of TB was altered by the treatment with 5-FU through a metabolic process, which may be responsible for the decreased CYP2C6/11 expression at mRNA levels. |
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| Keywords: | CYP2C 5-fluorouracil metabolic elimination pharmacokinetics rat tolbutamide |
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