title: Pharmacokinetics of SDZ 64-412, a novel antiasthmatic agent, following intravenous, oral, and inhalation dosing in the rat.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Drug Safety, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936.
authors.forename: S B
authors.initials: SB
authors.lastname: Charnick
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.forename: L V
authors.initials: LV
authors.lastname: Athill
authors.forename: A H
authors.initials: AH
authors.lastname: Karara
authors.forename: F L
authors.initials: FL
authors.lastname: Tse
authors.forename: D T
authors.initials: DT
authors.lastname: Lau
mesh_terms: 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
chemical_list: D007546:Isoquinolines; D010972:Platelet Activating Factor; C057722:SDZ 64-412