Oral idazoxan bioavailability in rat. Relevance of intestinal and hepatic first-pass effect.

The alpha 2-antagonist idazoxan (2-(2-(1,4-benzodioxanyl)-2-imidazoline) was administered iv, hepatoportally, and orally to Sprague-Dawley rats at 1, 3, and 10 mg/kg. Idazoxan plasma levels were determined by a HPLC method. A noncompartmental treatment of data was used to estimate the main pharmacokinetic parameters. After iv administration, idazoxan exhibited a linear kinetic profile. Half-life and mean residence time values ranged from 24.4 to 27.9 and from 34.2 to 40.5 min, respectively. Total plasma clearance values and volume of distribution at steady state values ranged from 0.057 to 0.078 (liters/kg)/min and 1.95 to 3.18 liters/kg, respectively. After the oral administration of idazoxan, time to peak values ranged from 5 to 10 min. When the oral 10 mg/kg dose was compared with both 1 and 3 mg/kg doses, significant statistical differences were observed in AUC levels and in dose-normalized peak concentration values (p less than 0.05, t test). Bioavailability values obtained after the oral administration of idazoxan ranged from 12.6 to 31.5%. The bioavailability range observed after the hepatoportal administration exceeded largely and significantly the range denoted after the oral route and displayed a saturable character already noted at the 3 mg/kg dose (p less than 0.01, t test).