Species variation in the enantioselective metabolism of tegafur to 5-fluorouracil among rats, dogs and monkeys

• Published in: Journal of pharmacy and pharmacology 2014-12, Vol.66 (12), p.1686-1697
• Main Authors: Yamamiya, Ikuo, Yoshisue, Kunihiro, Ishii, Yuji, Yamada, Hideyuki, Yoshida, Ken-ichiro
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - chemistry; Antimetabolites, Antineoplastic - metabolism; Biological Availability; biopharmaceutics and drug disposition; Cytochrome P-450 Enzyme System - metabolism; Dogs; Fluorouracil - blood; Fluorouracil - chemistry; Fluorouracil - metabolism; Injections, Intravenous; Macaca fascicularis; Male; Metabolic Clearance Rate; Metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; other topics; pharmacokinetics and drug disposition; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Rats, Sprague-Dawley; Species Specificity; Stereoisomerism; Tegafur - blood; Tegafur - chemistry; Tegafur - metabolism
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12304

Objectives Tegafur (FT), a pro‐drug of 5‐fluorouracil (5‐FU), is a racemate consisting of two enantiomers, R and S‐FT. The aim of this study was to clarify interspecies variation in the enantioselective metabolism of FT. Methods Plasma concentrations of FT enantiomers were determined in rats, dogs and monkeys following intravenous and oral dosing of the racemate (5 mg/kg). In addition, the enzymatic conversion of FT enantiomers to 5‐FU was assayed using hepatic preparations. Key findings Metabolic clearance of R‐FT was higher than that of S‐FT in rats and monkeys, but S‐FT was the preferential substrate for dogs. An inhibition study revealed that cytochrome P450 is primarily responsible for the enantioselective metabolism of FT in rats and dogs. In contrast, in monkeys, thymidine phosphorylase was a determinant of the enantioselectivity in FT metabolism. Although oral bioavailability was not enantioselective, in‐vitro and in‐vivo kinetic studies suggested that the enantioselectivity in the hepatic intrinsic clearance of FT directly influences the body clearance in all animal species examined. Conclusions The interspecies variations were observed in the enantioselective pharmacokinetics of FT, and the in‐vivo enantioselectivity could be extrapolated from the in‐vitro metabolic activities.