Toxicity of single-dose oral gemcitibine in mice.

Abstract

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The present study was conducted to determine the single-dose toxicity and toxicokinetics of gemcitabine when administered orally to mice. Gemcitabine hydrochloride, an intravenously administered chemotherapeutic antimetabolite, is a potent and specific oncolytic used for the treatment of cancer. The antiproliferative mechanism of the drug involves inhibition of DNA replication and repair by inhibiting DNA synthesis and by blocking repair mechanisms through masked chain termination. CD-1 mice (10/sex/group) were given a single oral (gavage) gemcitabine dose of 167, 333, or 500 mg/kg, and mice were euthanized 4 or 14 days postdose to determine the acute cytotoxic effects and the reversibility of compound-related effects, respectively. Data from this study were compared to data from previously conducted toxicology studies. Orally administered gemcitabine was rapidly absorbed with a time-to-peak plasma concentration of approximately 0.5 to 1.0 hours. Consistent with IV administration, metabolism of gemcitabine to difluorodeoxyuridine (dFdU) after a single-oral dose was extensive, with high plasma concentrations of dFdU relative to gemcitabine. There were no consistent gender-related differences in gemcitabine toxicokinetics. Exposure (area under the concentration vs. time curve) and maximum plasma concentration values for both gemcitabine and dFdU were not dose proportional in the dose range examined. Compound-related deaths in mice given 333 or 500 mg/kg occurred 3 to 5 days after dosing. The mortality seen in this study was attributed to adverse intestinal lesions characterized by moderate-to-marked loss of mucosal epithelium (atrophic enteropathy) throughout the entire length of the intestinal tract. Comparable exposures via IV dosing in previous mouse studies did not result in death or gastrointestinal toxicity. The enteropathy was dose-responsive in incidence and severity, but with marked variation among individual mice within compound-treated groups. In some mice that were euthanized and necropsied 4 days postdose, the intestinal changes were characterized by mucosal epithelial regeneration resulting in a normal mucosal thickness. Due to the severity of the intestinal lesions, suspected acute time of onset, and marked variation among individual mice within dose groups, it is likely that local effects due to the route of administration were important for development of the enteropathy. The systemic toxicities observed in this study were typical of those seen at these exposure levels. In summary, a single-oral dose of gemcitabine at 167, 333, or 500 mg/kg caused dose-responsive adverse intestinal lesions at exposures that were previously tolerated when the compound was adminstered IV. Toxicokinetics and systemic toxicity were consistent with data from earlier IV mouse studies.