title: Altered tolbutamide pharmacokinetics by a decrease in hepatic expression of CYP2C6/11 in rats pretreated with 5-fluorouracil.
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.
authors.affiliation: a Laboratory of Clinical Pharmacy and Therapeutics , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan and.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Fukuno
authors.affiliation: a Laboratory of Clinical Pharmacy and Therapeutics , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan and.|b Laboratory of Practical Pharmacy and Pharmaceutical Care , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Nagai
authors.affiliation: a Laboratory of Clinical Pharmacy and Therapeutics , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan and.
authors.forename: Keita
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: a Laboratory of Clinical Pharmacy and Therapeutics , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mizobata
authors.affiliation: b Laboratory of Practical Pharmacy and Pharmaceutical Care , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Omotani
authors.affiliation: b Laboratory of Practical Pharmacy and Pharmaceutical Care , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Hatsuda
authors.affiliation: b Laboratory of Practical Pharmacy and Pharmaceutical Care , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Myotoku
authors.affiliation: a Laboratory of Clinical Pharmacy and Therapeutics , Faculty of Pharmacy, Osaka Ohtani University , Tondabayashi , Japan and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Konishi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2 / Q000378:metabolism*; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D039181:Steroid 16-alpha-Hydroxylase / Q000378:metabolism*; D014044:Tolbutamide / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D007004:Hypoglycemic Agents; D014044:Tolbutamide; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D005472:Fluorouracil
keywords: 5-fluorouracil; CYP2C; metabolic elimination; pharmacokinetics; rat; tolbutamide