title: Pharmacokinetic modeling of species-dependent enhanced bioavailability of trifluorothymidine by thymidine phosphorylase inhibitor.
abstract: TAS-102, a new oral drug, is composed of an antitumor drug, alpha,alpha,alpha-trifluorothymidine (FTD), and its metabolic inhibitor, 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI). It has been reported that the oral administration of TAS-102 increases the AUC of FTD in rodents and monkeys in different manners. In this study, a pharmacokinetic model was developed, in an attempt to evaluate the bioavailability of FTD in these animals after the co-administration of TPI. Since TPI inhibits FTD metabolism competitively, a time-dependent as well as concentration-dependent model for the hepatic intrinsic clearance of FTD was developed including the time courses of both FTD and TPI. Based on this modeling, we were able to quantitatively explain the TPI dose-dependent enhancement of AUC of FTD in monkeys, while little increase was observed in rats. These results are consistent to observations that thymidine phosphorylase (TPase) is predominantly expressed in monkeys; while uridine phosphorylase (UPase) is superior to TPase in rats. Since TPase is also predominantly expressed in humans, the pharmacokinetic model developed in this study can be used to explain the bioavailability of TAS-102 in humans.
authors.affiliation: Laboratory for Molecular Design of Pharmaceutics and COE Program in the 21st Century, Graduate School of Pharmaceutical Sciences, Hokkaido University, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Keizou
authors.initials: K
authors.lastname: Kuwata
authors.forename: Sekio
authors.initials: S
authors.lastname: Nagayama
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Yamashita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kamiya
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Harashima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D008954:Models, Biological; D011759:Pyrrolidines; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013941:Thymine; D014271:Trifluridine / Q000493:pharmacokinetics*; D014498:Uracil / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D004338:Drug Combinations; D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C000613803:trifluridine tipiracil drug combination; D014498:Uracil; D013939:Thymidine Phosphorylase; D013941:Thymine; D014271:Trifluridine