DISPOSITION OF L-738,167, A POTENT AND LONG-ACTING FIBRINOGEN RECEPTOR ANTAGONIST, IN DOGS - DOSE-DEPENDENT PHARMACOKINETICS

L-738,167 is a potent and long-acting fibrinogen receptor antagonist a nd may be useful for treatment of chronic thrombotic occlusive disorde rs. The purposes of this study were to characterize the metabolism and disposition of L-738,167, and to investigate factors affecting its ph armacokinetic behaviors in dogs, one of the animal models used in phar macological and toxicological studies. In vitro and in vivo experiment s indicated that L-738,167 was not metabolized to any appreciable exte nt in dogs. Biliary excretion was found to be the major route (similar to 75%) of drug elimination. Following 1 and 3 mu g/kg iv doses, bloo d 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 vol ume. Blood pharmacokinetics in the dose range of 3-250 mu g/kg were do se-dependent; both CL(B) and Vd(ss,B) for L-738,167 increased markedly with increasing doses. However, the terminal half-life (t 1/2) was do se-independent, with a mean value of similar to 4 days. L-738,167 was found to bind negligibly to dog plasma proteins. Determinations of who le blood (WB), platelet-rich plasma, and platelet-poor plasma concentr ations after several intravenous doses of [H-3]L-738,167 revealed sign ificant concentration-dependent binding of the compound to platelets. Kinetic analysis of the platelet binding indicated that L-738,167 was bound to dog platelets with high affinity (apparent K-d similar to 1 n M platelet-poor plasma concentration) and relatively low capacity (sim ilar to 70 nM WB concentration). Findings are consistent with the bind ing kinetics of L-738,167 to glycoprotein IIb/IIIa (GP IIb/IIIa) recep tor, supporting that GP IIb/IIIa was the primary binding component on the platelets. It was concluded that the dose-dependent pharmacokineti cs of L-738,167 were the consequence of the concentration-dependent dr ug-platelet binding. Due to this extensive platelet binding, L-738,167 , when given in therapeutic doses or lower, resided primarily in the v ascular compartment-the site of pharmacological action. At doses excee ding the receptor binding capacity, the excess amount or the unbound d rug was eliminated rapidly. In all cases, the equally long t 1/2 of L- 738,167 was also a consequence of the high-affinity binding to platele ts, in good agreement with its prolonged pharmacodynamic profile.