Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5-Oxo-6,8,11,14-eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys

The potent eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of ω2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists.