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 (∼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 ∼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 ∼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.