PT - JOURNAL ARTICLE AU - Stephan A. Veltkamp AU - Dick Pluim AU - Olaf van Tellingen AU - Jos H. Beijnen AU - Jan H. M. Schellens TI - Extensive Metabolism and Hepatic Accumulation of Gemcitabine After Multiple Oral and Intravenous Administration in Mice AID - 10.1124/dmd.108.021048 DP - 2008 Aug 01 TA - Drug Metabolism and Disposition PG - 1606--1615 VI - 36 IP - 8 4099 - http://dmd.aspetjournals.org/content/36/8/1606.short 4100 - http://dmd.aspetjournals.org/content/36/8/1606.full SO - Drug Metab Dispos2008 Aug 01; 36 AB - In a clinical study with oral gemcitabine (2′,2′-difluorodeoxycytidine, dFdC), we found that gemcitabine was hepatotoxic and extensively metabolized to 2′,2′-difluorodeoxyuridine (dFdU) after continuous oral dosing. The main metabolite dFdU had a long terminal half-life after oral administration. Our hypothesis was that dFdU and/or phosphorylated metabolites of gemcitabine accumulated in the liver after multiple oral dosing. In this study, mice were treated with oral or i.v. dFdC at a single dose (1qd×1d) or at multiple doses once daily for 7 days (1qd×7d) or seven times daily (7qd×1d). Blood, liver, kidneys, and lungs were collected at several time points. Urine samples were collected after i.v. dFdC, and peripheral blood mononuclear cells were collected 7qd×1d dosing of dFdC. The nucleosides dFdC and dFdU as well as the nucleotides gemcitabine monophosphate (dFdC-MP), diphosphate, and triphosphate (dFdC-TP) and dFdU monophosphate, diphosphate (dFdU-DP), and triphosphate (dFdU-TP) were simultaneously quantified by high-performance liquid chromatography with ultraviolet and radioisotope detection. We demonstrate that phosphorylated metabolites of both dFdC and dFdU are formed in mice, primarily consisting of dFdC-MP, dFdC-TP, and dFdU-TP. Multiple dosing of dFdC leads to substantial hepatic and renal accumulation of dFdC-TP and dFdU-TP, which have a more pronounced liver accumulation after oral than after i.v. dosing. The presence of dFdC-MP, dFdC-TP, and dFdU-TP in plasma and urine suggests efflux of these potentially toxic metabolites. Our results show that dFdU, dFdC-TP, and dFdU-TP accumulate in the liver after multiple dosing of dFdC in mice and might be associated with hepatotoxicity of oral dFdC in patients. The American Society for Pharmacology and Experimental Therapeutics