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 µg ml⁻¹, but lower at higher concentrations. Although radioactivity was rapidly distributed into rat tissues, V_ss was low (about 0.15 l kg⁻¹) in both rat and dog. Nevertheless, reparixin was more rapidly eliminated in rats (t_½ ∼ 0.5 h) than in dogs (t_½ ∼ 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.

Key words::

• Chemokine CXCL8 inhibitor
• metabolism
• pharmacokinetics
• reparixin
• ischaemia-reperfusion injury
• species differences

Acknowledgements

The authors gratefully acknowledge the technical assistance of Dr S. Johnson for performing the TLC work, Ms T. Houchen and Mr R. A. Shabir for QWBA, and Mr I. Ward, Mr A. Roth and Mr A. Miller for assistance with the bioanalysis. Part of this work was presented in poster form at the European ISSX Meeting, Nice, France, in June 2005.