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Pharmacokinetics of Gemcitabine and Metabolites in a Patient with Double-Sided Nephrectomy: A Case Report and Review of the Literature

^aDepartment of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands; ^bDivision of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; ^cDepartment of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands; ^dDivision of Drug Toxicology, Section of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

Key Words. Gemcitabine • Hemodialysis

Correspondence: Correspondence: Stijn Koolen, Pharm.D., Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute and Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Telephone: 31-20-512-4652; Fax: 31-20-512-4753; e-mail: s.koolen{at}nki.nl

Received June 11, 2009; accepted for publication August 7, 2009.

Stijn L.W. Koolen: None; Alwin D.R. Huitema: None; Robert S. Jansen: None; Theo van Voorthuizen: None; Jos H. Beijnen: None; Willem M. Smit: None; Jan H.M. Schellens: None.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors or independent peer reviewers.

Case. A patient with complete renal failure as a result of urothelial cell carcinoma–related nephrectomy of both kidneys received palliative chemotherapy with carboplatin and gemcitabine.

Treatment. The patient received gemcitabine at 1,000 mg/m² followed by carboplatin at 100 mg. Shortly after, he underwent hemodialysis. The pharmacokinetics of gemcitabine and metabolites in plasma and in peripheral blood mononuclear cells were monitored.

Results. Double-sided nephrectomy and hemodialysis had no influence on gemcitabine pharmacokinetics; however, a high exposure was seen for the main metabolite, difluordeoxyuridine (dFdU) (area under the concentration–time curve, 0–51 hours, 844 µg/ml·hour). During hemodialysis, plasma concentrations of dFdU were reduced by 50%. High concentrations of intracellular phosphorylated metabolites (gemcitabine triphosphate and dFdU triphosphate) were observed: 228 pmol/10⁶ cells and 47 pmol/10⁶ cells, respectively. The patient tolerated the regimen poorly; adverse events included grade 4 thrombocytopenia.

Conclusion. Hemodialysis effectively reduced plasma concentrations of dFdU. Furthermore, high concentrations of intracellular phosphorylated metabolites may be related to double-sided nephrectomy, resulting in poor tolerability of gemcitabine.