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Drug Metabolism and Disposition Fast Forward
First published on May 19, 2008; DOI: 10.1124/dmd.108.021048

0090-9556/08/3608-1606-1615$20.00
DMD 36:1606-1615, 2008

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Extensive Metabolism and Hepatic Accumulation of Gemcitabine After Multiple Oral and Intravenous Administration in Mice

Stephan A. Veltkamp, Dick Pluim, Olaf van Tellingen, Jos H. Beijnen, and Jan H. M. Schellens

Division of Experimental Therapy (S.A.V., D.P., J.H.M.S.) and Department of Clinical Pharmacology (S.A.V., J.H.M.S.), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands (O.v.T.); Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands (J.H.B.); and Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (J.H.B., J.H.M.S.).

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 (1qdx1d) or at multiple doses once daily for 7 days (1qdx7d) or seven times daily (7qdx1d). 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 7qdx1d 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.

Address correspondence to: Dr. Sander Veltkamp, Division of Experimental Therapy, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. E-mail: sander.veltkamp{at}nl.astellas.com






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