The pharmacokinetics and bioavailability of L-751,164, an ethyl ester prodrug of a potent fibrinogen receptor antagonist, L-742,998, were studied in beagle dogs and rhesus monkeys. In both species, L-751,164 exhibited high clearance. After an intravenous dose, L-751,164 was converted to the parent L-742,998 to the extent of approximately 20% in dogs and 90% in monkeys. After oral administration of the prodrug, however, the bioavailability, measured either as the prodrug or as the active parent, was < 5% in both species. Several experiments were conducted subsequently to investigate possible causes for the observed similarities in the low oral bioavailability of the prodrug between species despite its differences in the in vivo conversion. In vitro metabolism studies using dog liver subcellular fractions indicated extensive metabolism of L-751,164 to metabolites other than L-742,998. Kinetically, L-742,998 formation accounted only for approximately 25% of the prodrug disappearance. In contrast, monkey liver preparations converted L-751,164 exclusively and rapidly to L-742,998. Good agreement between the in vitro hepatic metabolism and the in vivo observations suggests that liver was the major eliminating organ after intravenous administration of the prodrug in both species. In dogs, this suggestion was further supported by low bioavailability of the prodrug (20%) and the parent (below detection limit) after intraportal administration of the prodrug. In vitro metabolism of L-751,164 using intestinal S9 fractions revealed substantial metabolism in monkeys, but not in dogs. Several NADPH-dependent metabolites were observed with monkey intestinal preparation, with the parent L-742,998 being the minor product (approximately 25-30%). Furthermore, L-751,164 was shown, by means of an in vitro Caco-2 cell, and in situ rat intestinal loop models, to be highly permeable to intestinal barriers. Collectively, these results suggest that the apparent species differences in the prodrug conversion observed in vivo likely were due to species differences in the hepatic metabolism of the prodrug. In both species, the high first-pass metabolism of the prodrug, and the extensive conversion of the prodrug to metabolic products other than the parent contributed, at least in part, to the low bioavailability of the prodrug and active parent, respectively, obtained after an oral dose of the prodrug. The latter process was species-dependent, involving primarily the hepatic first-pass elimination in dogs and the intestinal first-pass metabolism in monkeys.