title: Pharmacokinetics and excretion of the 21-aminosteroid antioxidant U-74006F in rat and perfused rat liver.
abstract: U-74006F, 21-(4-(2,6-dipyrrolidinyl-4-pyrimidinyl)-1-piperazinyl)-16 alpha-methylpregan-1,4,9(11)-triene monomethane sulfonate, is currently under development for the treatment of human central nervous system trauma and ischemia. The iv pharmacokinetics and excretion of 14CU-74006F (labeled in the 16 alpha-methyl group) and 3HU-74006F (labeled in a pyrrolidine ring) were investigated in the young adult Sprague-Dawley rat and the perfused rat liver. Following a 3 mg/kg iv bolus dose, plasma levels of 14CU-74006F declined biexponentially with alpha and beta half-times of 8 and 70 min, respectively. The terminal phase volume of distribution was 5.1 liters/kg and the plasma clearance was 51 ml/min/kg, which is similar to the in vivo hepatic plasma flow. Plasma levels of total 14C-labeled metabolites quickly exceeded levels of parent drug and declined with a terminal phase half-time of 50 hr. Greater than 90% of the 14C and 3H doses was excreted in feces with terminal phase half-times of 107 and 46 hr, respectively. Consistent with high hepatic clearance, the oral solution bioavailability of U-74006F was 16%, and the hepatic extraction efficiency of U-74006F from 3% bovine serum albumin (w/v) medium in the perfused liver was 80-86% under nonsaturating conditions at physiological flows. U-74006F was rapidly metabolized in the perfused liver and excreted in bile as metabolites. The biliary excretion mechanism was more easily saturated than hepatic uptake and metabolism, with the consequence that, at pharmacologically relevant perfusate levels of drug, metabolites accumulated in the liver and effluxed into the perfusate.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Drug Metabolism Research, Upjohn Company, Kalamazoo, MI 49001.
authors.forename: J W
authors.initials: JW
authors.lastname: Cox
authors.forename: P G
authors.initials: PG
authors.lastname: Larson
authors.forename: M A
authors.initials: MA
authors.lastname: Wynalda
authors.forename: V K
authors.initials: VK
authors.lastname: Sood
authors.forename: M T
authors.initials: MT
authors.lastname: Verburg
authors.forename: R N
authors.initials: RN
authors.lastname: Pullen
mesh_terms: D000818:Animals; D005260:Female; D006207:Half-Life; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors*; D008099:Liver / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D011281:Pregnatrienes / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D008054:Lipid Peroxides; D011281:Pregnatrienes; C053355:tirilazad