Abstract

l-738,167 is a potent and long-acting fibrinogen receptor antagonist and may be useful for treatment of chronic thrombotic occlusive disorders. The purposes of this study were to characterize the metabolism and disposition of l-738,167, and to investigate factors affecting its pharmacokinetic behaviors in dogs, one of the animal models used in pharmacological and toxicological studies. In vitro and in vivoexperiments indicated that l-738,167 was not metabolized to any appreciable extent in dogs. Biliary excretion was found to be the major route (∼75%) of drug elimination. Following 1 and 3 μg/kg iv doses, blood pharmacokinetics of l-738,167 were linear. Total blood clearance (CL_B ) was much lower than hepatic blood flow, and the apparent volume of distribution at steady-state (Vd_ss,B ) was comparable with blood volume. Blood pharmacokinetics in the dose range of 3–250 μg/kg were dose-dependent; both CL_B andVd_ss,B for l-738,167 increased markedly with increasing doses. However, the terminal half-life (t_½) was dose-independent, with a mean value of ∼4 days. l-738,167 was found to bind negligibly to dog plasma proteins. Determinations of whole blood (WB), platelet-rich plasma, and platelet-poor plasma concentrations after several intravenous doses of [³H]l-738,167 revealed significant concentration-dependent binding of the compound to platelets. Kinetic analysis of the platelet binding indicated thatl-738,167 was bound to dog platelets with high affinity (apparent K_d ∼ 1 nM platelet-poor plasma concentration) and relatively low capacity (∼70 nM WB concentration). Findings are consistent with the binding kinetics ofl-738,167 to glycoprotein IIb/IIIa (GP IIb/IIIa) receptor, supporting that GP IIb/IIIa was the primary binding component on the platelets. It was concluded that the dose-dependent pharmacokinetics ofl-738,167 were the consequence of the concentration-dependent drug-platelet binding. Due to this extensive platelet binding, l-738,167, when given in therapeutic doses or lower, resided primarily in the vascular compartment—the site of pharmacological action. At doses exceeding the receptor binding capacity, the excess amount or the unbound drug was eliminated rapidly. In all cases, the equally long t_½ ofl-738,167 was also a consequence of the high-affinity binding to platelets, in good agreement with its prolonged pharmacodynamic profile.