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Clinical Pharmacology

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

^aDivision of Experimental Therapy and ^bDepartment of Clinical Pharmacology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; ^cDepartment of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands; ^dFaculty of Science, Department of Pharmaceutical Sciences, Section of Biomedical Analysis, Division of Drug Toxicology, Utrecht University, Utrecht, The Netherlands

Key Words. Gemcitabine • Pharmacology • Fixed dose rate • Clinical activity

Correspondence: Correspondence: Stephan A. Veltkamp, Pharm.D., Division of Experimental Therapy, NKI-AvL, Postbus 90203, 1006 BE, Amsterdam, The Netherlands. Telephone: 31-20-512-2047; Fax: 31-20-512-2050; e-mail: s.veltkamp{at}nki.nl

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

Gemcitabine is frequently used in the treatment of patients with solid tumors. Gemcitabine is taken up into the cell via human nucleoside transporters (hNTs) and is intracellularly phosphorylated by deoxycytidine kinase (dCK) to its monophosphate and subsequently into its main active triphosphate metabolite 2',2'-difluorodeoxycytidine triphosphate (dFdCTP), which is incorporated into DNA and inhibits DNA synthesis. In addition, gemcitabine is extensively deaminated to 2',2'-difluorodeoxyuridine, which is largely excreted into the urine. High expression levels of human equilibrative nucleoside transporter type 1 were associated with a significantly longer overall survival duration after gemcitabine treatment in patients with pancreatic cancer.

Clinical studies in blood mononuclear and leukemic cells demonstrated that a lower infusion rate of gemcitabine was associated with higher intracellular dFdCTP levels. Prolonged infusion of gemcitabine at a fixed dose rate (FDR) of 10 mg/m² per minute was associated with a higher intracellular accumulation of dFdCTP, greater toxicity, and a higher response rate than with the standard 30-minute infusion of gemcitabine in patients with pancreatic cancer.

In the current review, we discuss the molecular pharmacology of nucleoside analogues and the influence of hNTs and dCK on the activity and toxicity of gemcitabine, which is the basis for clinical studies on FDR administration, and the results of FDR gemcitabine administration in patients. These findings might aid optimal clinical application of gemcitabine in the future.