ANALYSIS OF METABOLITE KINETICS BY DECONVOLUTION AND IN VIVO-IN VITROCORRELATIONS OF METABOLITE FORMATION RATES - STUDIES OF FIBRINOGEN RECEPTOR ANTAGONIST ESTER PRODRUGS

The pharmacokinetics of L-767,679, a potent fibrinogen receptor antago nist, were characterized following administration of its ethyl ester p rodrug to dogs and monkeys. Deconvolution analysis was performed to de termine the rate and extent of (1) the formation of L-767,679 from the prodrug in the systemic circulation, (2) the composite input (systemi c and presystemic) of L-767,679 to the general circulation after oral administration of the prodrug, (3) the oral input of the prodrug, and (4) the input of the presystemically formed L-767,679 following oral a dministration of the prodrug. The results indicated that there were sp ecies differences in the kinetics of the disposition of L-767,679 and its prodrug. In dogs, the prodrug was absorbed faster than it was conv erted to the active drug, and the presystemic formation of L-767,679 c ontributed to about one-half of the total input of L-767,679 following oral administration of the prodrug. In monkeys, the low input of L-76 7,679 following oral administration of the prodrug was not due to an i nefficient formation of L-767,679 in the systemic circulation but rath er to the low oral bioavailability of the prodrug. Virtually all of th e total oral input of L-767,679 following administration of its prodru g to monkeys resulted from the presystemic metabolism of the prodrug. These results were consistent with the finding in monkeys that the est er prodrug underwent extensive transformation to metabolites other tha n L-767,679. In addition, the present study also demonstrated a correl ation between in vivo formation rates of L-767,679 determined using de convolution analysis following its ethyl, methyl, and isopropyl esters in dogs and the ethyl ester in monkeys and in vitro formation rates o f L-767,679 obtained following incubations of the corresponding esters with dog and monkey liver microsomes. The results suggested that deco nvolution and/or convolution analysis together with in vitro metabolis m results could potentially be used to predict in vivo formation rates of other ester prodrugs of L-767,679 and also plasma concentrations o f L-767,679 as a function of time, following administration of its pro drugs.