Route-dependent nonlinear pharmacokinetics of a novel HIV protease inhibitor: Involvement of enzyme inactivation

L-754,394, a furanopyridine derivative, is an experimental HIV protease inh ibitor. Previous studies from this laboratory have demonstrated that L-754, 394 is cleared very rapidly in animals, and that this drug is a potent mech anism-based inactivator (suicide inhibitor) for CYP3A4 in human liver micro somes. Because L-754,394 is a high-clearance drug and an enzyme inactivator , it is expected that this drug will be subject to significant first-pass m etabolism, and that the degree of enzyme inactivation will be dependent not only on the dose, but also on the route of administration. The purpose of this study is to examine the effects of dose and route of administration on the kinetics of L-754,394 using rats and dogs as animal models. In both ra ts and dogs, L-754,394 exhibited marked dose-dependent pharmacokinetics aft er i.v. and oral administration. Irrespective of i.v. or oral administratio n, the area under the plasma concentration-time curve from zero to infinity increased with dose in a greater than proportional manner. However, the ma gnitude of area under the plasma concentration-time curve from zero to infi nity increase was much greater after oral dosing than after i.v. administra tion, indicating route-dependent pharmacokinetics. Data from in vitro and i n vivo studies suggested that the dose- and route-dependent pharmacokinetic s were due mainly to the inactivation (destruction) of the enzymes responsi ble for its own metabolism.