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.