PHARMACOKINETICS OF SDZ-64-412, A NOVEL ANTIASTHMATIC AGENT, FOLLOWING INTRAVENOUS, ORAL, AND INHALATION DOSING IN THE RAT

The pharmacokinetics of SDZ 64-412, an antiasthmatic agent, were inves tigated following intravenous, oral, and inhalation dosing in rats. C- 14-SDZ 64-412 was administered intravenously (2.75 mg kg(-1)) and oral ly (5.5 mg kg(-1), 110 mg kg(-1)), whereas non-radiolabeled drug (5.04 mg kg(-1)) was-administered using nose-only inhalation chambers. Radi oactivity and parent drug concentrations in blood, lung, and excreta w ere determined at designated times post-dose. SDZ 64-412 was rapidly a nd extensively (similar to 80%) absorbed following both oral doses, al though absorption appeared to be prolonged with increasing dose. The a bsorbed drug was shown to undergo extensive and saturable first-pass m etabolism. The bioavailability of the parent drug, calculated by dose- normalized AUC and deconvolution methods, was only 10-15% from the low dose, but increased to similar to 40% following the high dose. Follow ing inhalation dosing, SDZ 64-412 concentrations in blood and lungs in creased rapidly, and did nor decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of similar to 40 %, and AUC of the drug in lungs was approximately 25 times greater tha n in blood. In general, SDZ 64-412 was extensively distributed and rap idly eliminated from the systemic circulation. Biliary excretion was t he predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of deli very of SDZ 64-412.