RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 794
OP 797
VO 29
IS 6
A1 Hiroshi Yamazaki
A1 Tomoko Komatsu
A1 Kei Takemoto
A1 Noriaki Shimada
A1 Miki Nakajima
A1 Tsuyoshi Yokoi
YR 2001
UL http://dmd.aspetjournals.org/content/29/6/794.abstract
AB 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