Disposition and tissue levels of [3H]vindesine in rats.

The excretion, blood levels, and tissue distribution of [3H]vindesine have been studied in the rat. After an i.v. administration of 500 microgram/kg. [3H]vindesine was found to be distributed very rapidly to tissues. After the distribution phase, blood levels declined with a half-life near 10 hr. Excretion was mainly via the bile, and [3H]vindesine and its metabolites in bile were poorly reabsorbed in the gastrointestinal tract. Levels were relatively high in most tissues studied but appeared to be efficiently cleared from all tissues except thymus and testes. Uptake into peripheral nerves was considerably higher than into the central nervous system.

Mechanism of the dealkylation of tertiary amines by hepatic oxygenases. Stable isotope studies with 1-benzyl-4-cyano-4-phenylpiperidine.

The microsomal oxidative dealkylation of 1-benzyl-4-cyano-4-phenylpiperidine has been studied and the source of oxygen shown to be molecular oxygen. The rate of debenzylation was decreased by substituting deuterium for hydrogen in the methylene portion of the benzyl group. The isotope effect was measured by comparison of the reaction rates of the d0 and d2 compounds 1a and 1b and also of the d5 and d7 compounds 1c and 1d. Determination of the reaction rates for various mixtures of labeled and unlabeled species allowed the rates for 0 (kH) and 100 mol % (kD) to be accurately obtained. A primary isotope effect of 1.46 was observed when the methylene hydrogens of benzyl were replaced by deuterium. No secondary isotope was observed when the aromatic hydrogens of benzyl were replaced by deuterium. The results of this study are consistent with a mechanism involving direct hydroxylation at the benzyl methylene position in a rate-determining step.

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.