Pharmacokinetic Modeling of Species-dependent Enhanced Bioavailability of Trifluorothymidine by Thymidine Phosphorylase Inhibitor

TAS-102, a new oral drug, is composed of an antitumor drug, α,α,α-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 i...

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Published in:DRUG METABOLISM AND PHARMACOKINETICS 2004, Vol.19 (3), p.206-215
Main Authors: Tsuchiya, Hiroyuki, Kuwata, Keizou, Nagayama, Sekio, Yamashita, Kazumasa, Kamiya, Hiroyuki, Harashima, Hideyoshi
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Biological Availability
Computer Simulation
Dose-Response Relationship, Drug
Drug Combinations
drug-drug interaction
Enzyme Inhibitors - pharmacokinetics
FTD
Macaca fascicularis
Male
Models, Biological
Rats
Rats, Sprague-Dawley
simulation
Species Specificity
TAS-102
Thymidine Phosphorylase - antagonists & inhibitors
Thymidine Phosphorylase - metabolism
TPI
Trifluridine - pharmacokinetics
Uracil - analogs & derivatives
Uracil - pharmacokinetics
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Summary:TAS-102, a new oral drug, is composed of an antitumor drug, α,α,α-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.
ISSN:1347-4367
1880-0920
DOI:10.2133/dmpk.19.206