IN-VITRO AND IN-VIVO EVALUATIONS OF THE METABOLISM, PHARMACOKINETICS,AND BIOAVAILABILITY OF ESTER PRODRUGS OF L-767,679, A POTENT FIBRINOGEN RECEPTOR ANTAGONIST - AN APPROACH FOR THE SELECTION OF A PRODRUG CANDIDATE

The present study demonstrates the utility of an in vitro-in vivo corr elative approach in the selection of an optimum prodrug candidate of L -767,679 olinone-2-yl]acetyl}-3(S)-(ethynyl)-beta-alanine), a potent f ibrinogen receptor antagonist. As an initial screening step, a compara tive in vitro hepatic metabolism study was conducted for L-767,679 and a series of aliphatic and aromatic ester prodrugs in dogs, monkeys, a nd humans. In all species, the active acid L-767,679, but not the este r prodrugs, was resistant to metabolism. Only the methyl, ethyl, and i sopropyl esters were converted exclusively to the active acid in liver microsomal preparations from dogs and humans, and thus were selected for further studies. In the preparations from monkeys, all of the este rs investigated were metabolized efficiently to both the active acid a nd several other products. The absolute formation rates of L-767,679 f rom the esters followed the rank order: methyl similar to ethyl > isop ropyl in all species, and in humans > dogs for the three esters. The t hree ester prodrugs did not undergo appreciable hydrolysis in blood or upon incubation with intestinal S9 from any of the studied species. I n vivo evaluation of the previous three aliphatic esters in dogs and m onkeys supported the in vitro findings. L-767,679 was metabolically st able in both dogs and monkeys. After intravenous administration of the prodrugs to either species, the extent of acid formation was higher i n dogs than in monkeys. In addition, the extent of L-767,679 formed fr om these prodrugs followed the rank order: methyl similar to ethyl > i sopropyl, Similar results were obtained after oral dosing of the prodr ugs, such that the bioavailability of L-767,679 was higher in dogs tha n in monkeys, and the bioavailability was higher after the ethyl ester than after the isopropyl prodrug in both species. In either species, both ethyl and isopropyl ester prodrugs were better absorbed than L-76 7,679. Overall, the results suggested that the bioavailability of the active acid after administration of an ester prodrug was dictated prim arily by two factors, viz.: 1) the relative rates of ester hydrolysis versus competing metabolic reactions and 2) the absolute rates of este r hydrolysis. In the case of L-767,679 prodrugs, absorption was not a limiting factor. Consequently, the bioavailability of L-767,679 after oral administration of the ester prodrugs would likely be greater in h umans than in dogs, and in humans would be higher with the ethyl ester than with the isopropyl ester. On this basis, the ethyl ester was con sidered as a promising candidate for clinical evaluation as a fibrinog en receptor antagonist prodrug.