Pharmacokinetics of gemcitabine and its primary metabolite in dogs after intravenous bolus dosing and its in vitro pharmacodynamics.

Abstract

Gemcitabine is a chemotherapeutic agent used to treat a variety of cancers in humans and dogs. In this study, the plasma pharmacokinetics of gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), were investigated in dogs after intravenous bolus gemcitabine doses of 3, 10, and 30 mg/kg. Furthermore, the intracellular accumulation of the active metabolite gemcitabine triphosphate, as a surrogate pharmacodynamic endpoint, was also determined in vitro in canine melanoma cells. Gemcitabine was characterized by linear kinetics, while dFdU dose proportionality remains unknown. The average gemcitabine clearance was 0.560 L/h.kg and volume of distribution at steady-state of 1.27 L/kg. The average terminal elimination half-life, depending on dose, ranged from 1.75 to 3.23 h. Plasma concentrations of dFdU peaked at approximately 2 h post-dosing. In vitro intracellular gemcitabine triphosphate accumulation was saturated with increasing extracellular gemcitabine concentrations. These data can be used to rationally design gemcitabine dosage regimes for canine oncology patients and as a basis for future investigations on the in vivo intracellular accumulation of gemcitabine triphosphate in dogs.

• Authors: K J Freise, T Martín-Jiménez
• Journal: Journal of veterinary pharmacology and therapeutics (J Vet Pharmacol Ther) Vol. 29 Issue 2 Pg. 137-45 (Apr 2006) ISSN: 0140-7783 [Print] England
• PMID: 16515668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimetabolites, Antineoplastic
• Floxuridine
• Deoxycytidine
• 2',2'-difluoro-2'-deoxyuridine
• Gemcitabine

Topics

• Animals
• Antimetabolites, Antineoplastic (metabolism, pharmacokinetics, pharmacology)
• Area Under Curve
• Deoxycytidine (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Dogs
• Female
• Floxuridine (analogs & derivatives, blood)
• Half-Life
• Metabolic Clearance Rate
• Tumor Cells, Cultured (drug effects)
• Gemcitabine