Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs.

Gemcitabine, 2'-deoxy-2',2'-difluorocytidine, is a broad spectrum oncolytic compound with antitumor activity in solid tumor models. The pharmacokinetics, metabolism, and disposition of gemcitabine was examined in mice, rats, and dogs. All three species metabolize gemcitabine by deamination to the uracil metabolite. However, deamination in the mouse and dog was more extensive than in the rat. The mouse deaminated gemcitabine rapidly with the plasma concentration maximum of the uracil metabolite of gemcitabine being attained at 15 min postdosing compared with approximately 3 and 6 hr in the dog and rat, respectively. The rapid deamination in the mouse was also reflected in the plasma half-life of the parent compound. The mouse exhibited the shortest plasma half-life, approximately 0.28 hr, contrasted with 2.14 and 1.38 hr half-lives in rat and dog, respectively. Plasma AUC for the uracil metabolite of gemcitabine was 73%, 10.5%, and 315% of that for gemcitabine in the mouse, rat, and dog, respectively. Tissue concentrations of gemcitabine-derived radioactivity in the rat and mouse indicated that gemcitabine was rapidly distributed throughout the body. Half-lives of radioactivity in tissues of both the rat and mouse were relatively short, with the longest tissue half-lives of 5.7 and 3.0 hr, respectively. Plasma protein binding is negligible in all three species. The major route of elimination is via the urine in all three species with 76-86% of the dose excreted in the first 24 hr. The predominant radiolabeled component isolated from urine was gemcitabine in the rat and its uracil metabolite in the mouse and dog.