THE BIOAVAILABILITY AND NONLINEAR PHARMACOKINETICS OF MK-679 IN HUMANS

MK-679 ethylamino)-3-oxopropyl)thio)methyl)thio)propanoic acid) is a p otent and specific LTD(4)-receptor antagonist. The disposition of MK-6 79 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma conc entration-time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differe ntial equations for a two-compartment model with linear tissue distrib ution and Michaelis-Menten elimination from the central compartment, i ndicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-depe ndent when given together with its S(+)-isomer, L-668,018. Thus, the d isposition of MK-679 in humans is dose-dependent regardless of the pre sence of its stereoisomer. Also, the bioavailability of MK-679 was det ermined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg C-14-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nea rly quantitative.