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Species differences in the biopharmaceutical properties of fuzapladib sodium monohydrate in rats, cats, and dogs


Pharmacy & Pharmacology International Journal
Satomi Onoue,1 Koji Higuchi,1,2 Chika Yamane,1 Ryota Tsukada,1 Kohei Yamada,1 Kenta Sasaki,2 Chikako Yoshida,2 Hiroshi Shikama,2 Hideyuki Sato1

Abstract

The present study aimed to characterize biopharmaceutical properties of fuzapladib sodium monohydrate, a new animal drug for acute pancreatitis, with a focus on species and gender differences. Fuzapladib sodium monohydrate (2 mg/kg of body weight) was administered subcutaneously or intravenously in male and female rats, cats, and dogs, and pharmacokinetic behavior was monitored by chromatographic analyses. With use of liver S9 fractions from each species, metabolism kinetics for fuzapladib were measured in vitro, with or without potent CYP inhibitors. After subcutaneous administration of fuzapladib sodium monohydrate (2 mg/kg), fuzapladib was rapidly absorbed in all the species tested (male), with Cmax values of 3.2 (rats), 6.6 (cats), and 14.7 µg/mL (dogs). Clearance of fuzapladib was significantly different between the species as evidenced by variable apparent elimination kinetics (male): 2.1, 0.30, and 0.13 h-1 for rats, cats, and dogs, respectively. Gender differences in pharmacokinetic behavior were not significant. Cytochrome P450 (CYP) inhibitors reduced metabolism of fuzapladib in liver S9 fraction from all three species, with significant differences in inhibitory patterns between species and various CYP inhibitors. Pharmacokinetic behavior of fuzapladib is variable depending on species, and this could be explained in part by metabolic transition.

Keywords

animal drug, fuzapladi sodium monohydrate, metabolism, pharmacokinetics, species difference

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