TY - JOUR T1 - Rat Cytochrome P450 1A and 3A Enzymes Involved in Bioactivation of Tegafur to 5-Fluorouracil and Autoinduced by Tegafur in Liver Microsomes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 794 LP - 797 VL - 29 IS - 6 AU - Hiroshi Yamazaki AU - Tomoko Komatsu AU - Kei Takemoto AU - Noriaki Shimada AU - Miki Nakajima AU - Tsuyoshi Yokoi Y1 - 2001/06/01 UR - http://dmd.aspetjournals.org/content/29/6/794.abstract N2 - Tegafur, an anticancer prodrug, is reported to be bioactivated to 5-fluorouracil (5-FU) by cytochrome P450 (P450) enzymes. Liver microsomal P450 enzymes involved in the biotransformation of tegafur into 5-FU in rats and the effect of tegafur in vivo on P450 levels in rats were investigated. Of 12 cDNA-expressed rat P450 enzymes tested, CYP1A2, CYP3A1, and CYP2C11 had high 5-FU formation rates from 100 μM and 1.0 mM tegafur concentrations. The contributions of CYP1A, CYP2C, and CYP3A enzymes to 5-FU formation in male rat liver microsomes were supported by immunoinhibition studies. 5-FU formation from tegafur, at substrate concentrations of 100 μM and 1.0 mM, was increased by intraperitoneal treatment of tegafur (50 mg/kg for 5 days) as well as by β-naphthoflavone, phenobarbital, and dexamethasone. Orally administered tegafur (100 mg/kg daily for 20 days) caused the induction of CYP2B (5-fold) and of CYP1A and CYP3A (∼2-fold) and of 5-FU formation (∼2-fold) in rat liver microsomes. These results suggest that CYP1A and CYP3A enzymes, autoinduced by tegafur, have important roles in 5-FU formation from tegafur in rat liver microsomes. Coadministration of tegafur and P450-inducing drugs could markedly enhance the biotransformation of tegafur into 5-FU via P450 induction. The American Society for Pharmacology and Experimental Therapeutics ER -