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.
Charnick
S B
SB
Department of Clinical Pharmacology, Drug Safety, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936.
Yu
Z
Z
Athill
L V
LV
Karara
A H
AH
Tse
F L
FL
Lau
D T
DT
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D007546:Isoquinolines; D010972:Platelet Activating Factor; C057722:SDZ 64-412