Disposition of flavodilol in laboratory animals.
The disposition of flavodilol, a novel antihypertensive agent, was investigated in rats, rabbits, and dogs following iv or oral administration of 14C-flavodilol or unlabeled drug. Peak, plasma levels occurred within 6 hours of an oral dose in all three species. Following an iv dose, plasma elimination half-lives of flavodilol in rats, rabbits, and dogs were 3.0, 3.0, and 4.0 hr, respectively. Total body clearances were 0.71 liter/hr/kg for the rat, 1.89 liters/hr/kg for the rabbit, and 3.07 liters/hr/kg for the dog. Renal clearances were a small fraction of total clearance at 0.042, and 0.114 liter/hr/kg for the rat and dog, respectively, suggesting extensive nonrenal clearance. The volumes of distribution of 3.04 for the rat, 8.10 for rabbit, and 18.13 liters/kg for dog are large, suggesting significant extravascular distribution of flavodilol. Following 10 and 50 mg/kg po doses of 14C-flavodilol in rats, recovery of total radioactivity after 79 hr was 100.7% and 88.4% of the dose, respectively, most of which was recovered in the feces (77.5% and 66.6%, respectively). Tissue distribution studies of 14C in rats at 1.5, 5, 24, and 48 hr after a single po dose of 10 mg/kg 14C-flavodilol showed that the majority of the radioactivity was in the gastrointestinal tract and organs of elimination at all time points. Less than 1% of the dose remained in the body at 48 hr. 14C-Flavodilol was administered to rats iv at 1 mg/kg and orally at 10 mg/kg to assess comparative (label vs. nonlabel) absorption and distribution characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)
Coan
M
M
Fisons Pharmaceuticals, Rochester, NY 14623.
Simmons
R
R
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D005419:Flavonoids / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D000959:Antihypertensive Agents; D005419:Flavonoids; C058114:flavodilol