SPECIES AND ORGAN DIFFERENCES IN FIRST-PASS METABOLISM OF THE ESTER PRODRUG L-751,164 IN DOGS AND MONKEYS - IN-VIVO AND IN-VITRO STUDIES

The pharmacokinetics and bioavailability of L-751,164, an ethyl ester prodrug of a potent fibrinogen receptor antagonist, L-742,998, were st udied in beagle dogs and rhesus monkeys. In both species, L-751,164 ex hibited high clearance. After an intravenous dose, L-751,164 was conve rted to the parent L-742,998 to the extent of similar to 20% in dogs a nd 90% in monkeys. After oral administration of the prodrug, however, the bioavailability, measured either as the prodrug or as the active p arent, was <5% in both species. Several experiments were conducted sub sequently to investigate possible causes for the observed similarities in the low oral bioavailability of the prodrug between species despit e its differences in the in vivo conversion. In vitro metabolism studi es using dog liver subcellular fractions indicated extensive metabolis m of L-751,164 to metabolites other than L-742,998. Kinetically, L-742 ,998 formation accounted only for similar to 25% of the prodrug disapp earance. In contrast, monkey liver preparations converted L-751,164 ex clusively and rapidly to L-742,998. Good agreement between the in vitr o hepatic metabolism and the in vivo observations suggests that liver was the major eliminating organ after intravenous administration of th e prodrug in both species. In dogs, this suggestion was further suppor ted by low bioavailability of the prodrug (20%) and the parent (below detection limit) after intraportal administration of the prodrug. In v itro metabolism of L-751,164 using intestinal S9 fractions revealed su bstantial metabolism in monkeys, but not in dogs. Several NADPH-depend ent metabolites were observed with monkey intestinal preparation, with the parent L-742,998 being the minor product (similar to 25-30%). Fur thermore, L-751,164 was shown, by means of an in vitro Caco-2 cell, an d in situ rat intestinal loop models, to be highly permeable to intest inal barriers. Collectively, these results suggest that the apparent s pecies differences in the prodrug conversion observed in vivo likely w ere due to species differences in the hepatic metabolism of the prodru g. In both species, the high first-pass metabolism of the prodrug, and the extensive conversion of the prodrug to metabolic products other t han the parent contributed, at least in part, to the low bioavailabili ty of the prodrug and active parent, respectively, obtained after an o ral dose of the prodrug. The latter process was species-dependent, inv olving primarily the hepatic first-pass elimination in dogs and the in testinal first-pass metabolism in monkeys.