Modulation of Gemcitabine (2′,2′-Difluoro-2′-Deoxycytidine) Pharmacokinetics, Metabolism, and Bioavailability in Mice by 3,4,5,6-Tetrahydrouridine

Abstract

Purpose:In vivo, 2′,2′-difluoro-2′-deoxycytidine (dFdC) is rapidly inactivated by gut and liver cytidine deaminase (CD) to 2′,2′-difluoro-2′-deoxyuridine (dFdU). Consequently, dFdC has poor oral bioavailability and is administered i.v., with associated costs and limitations in administration schedules. 3,4,5,6-Tetrahydrouridine (THU) is a potent CD inhibitor with a 20% oral bioavailability. We investigated the ability of THU to decrease elimination and first-pass effect by CD, thereby enabling oral dosing of dFdC.