Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773.