Species differences in the pharmacokinetics and metabolism of reparixin in rat and dog

Abstract

The pharmacokinetics and metabolism of reparixin (formerly repertaxin), a potent and specific inhibitor of the chemokine CXCL8, were investigated in rats and dogs after intravenous administration of [14C]-reparixin L-lysine salt. Protein binding of reparixin was investigated in vitro in rat, dog, rabbit, cynomolgus monkey and human plasma. Plasma protein binding of reparixin was >99% in the laboratory animals and humans up to 50 microg ml-1, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, Vss was low (about 0.15 l kg-1) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t1/2 approximately 0.5 h) than in dogs (t1/2 approximately 10 h). Systemic exposure in dog was due primarily to parent drug, but metabolites played a more prominent role in rat. Oxidation of the isobutyl side-chain was the major metabolic pathway in rat, whereas hydrolysis of the amide bond predominated in dog. Urinary excretion, which accounted for 80-82% of the radioactive dose, was the major route of elimination in both species, and biotransformation of reparixin was complete before excretion.

The Biochemistry of Drug Metabolism — An Introduction. Part 2. Redox Reactions and Their Enzymes

“…Our last case here is that of reparixin (c; 2.28), an inhibitor of the chemokine CXCL8 and a sobering metabolic example. Indeed and contrary to what could be expected based on the previous examples, the benzylic position was a minor site of oxidation, as were each of the enantiotopic CH 3 groups in the isobutyl chain [81]. Remarkably, the major site of CYP attack was the methine (CÀH) group.…”