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

Journal of Veterinary Pharmacology and Therapeutics
K J Freise, T Martín-Jiménez

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.

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Citations

Oct 7, 2009·Journal of Aerosol Medicine and Pulmonary Drug Delivery·Carlos O RodriguezPeter M Anderson
Jan 30, 2009·Journal of Veterinary Internal Medicine·P A DominguezB E Kitchell
Mar 21, 2009·Journal of Veterinary Internal Medicine·I Martinez-RuzafaB E Kitchell
Aug 2, 2012·American Journal of Veterinary Research·Joao Felipe de Brito GalvaoNongnuch Inpanbutr
Apr 25, 2008·Canadian Journal of Physiology and Pharmacology·Rui MinWan-Liang Lu
Jan 31, 2009·Veterinary and Comparative Oncology·L MarconatoE Zini
Mar 7, 2006·Journal of Veterinary Pharmacology and Therapeutics·K J Freise, T Martín-Jiménez
Jul 14, 2010·Mass Spectrometry Reviews·Robert S JansenJos H Beijnen

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