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 investigated following intravenous, oral, and inhalation dosing in rats. 14C-SDZ 64-412 was administered intravenously (2.75 mg kg-1) and orally (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. Radioactivity and parent drug concentrations in blood, lung, and excreta were determined at designated times post-dose. SDZ 64-412 was rapidly and extensively (approximately 80%) absorbed following both oral doses, although absorption appeared to be prolonged with increasing dose. The absorbed drug was shown to undergo extensive and saturable first-pass metabolism. 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 approximately 40% following the high dose. Following inhalation dosing, SDZ 64-412 concentrations in blood and lungs increased rapidly, and did not decline immediately after termination of dosing. The inhalation dose yielded a bioavailability of approximately 40%, and AUC of the drug in lungs was approximately 25 times greater than in blood. In general, SDZ 64-412 was extensively distributed and rapidly eliminated from the systemic circulation. Biliary excretion was the predominant route of radioactivity excretion. The present findings suggest that inhalation administration provides a viable means of delivery of SDZ 64-412.