Disposition of flavodilol in laboratory animals
Coan, M.; Simmons, R.
Drug Metabolism and Disposition the Biological Fate of Chemicals 17(4): 420-425
1989
ISSN/ISBN: 0090-9556 PMID: 2571483 Document Number: 327829
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 nenrenal 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. The apparent fraction of dose absorbed was 0.73 for the total 14C, compared to 0.53 for unlabeled parent drug. These differences are suggestive of significant presystemic metabolism. Regional brain distribution of 14C following oral dosing with 14C-flavodilol was significantly different from that following iv dosing. After an oral dose, the concentration of 14C in the hypothalamus was 77% higher than the average regional concentration. The cortex, however, had the highest concentration following iv dosing. The data are explored with an attempt to aid in the elucidation of a mechanism of action for flavodilol.