Disposition of the aldose reductase inhibitor AL01576 in rats.
The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4-mg/kg intravenous bolus and oral doses of [14C] AL01576 were administered and levels of radioactivity in blood, excreta, and various tissues were determined over a 168-h period. The decline of radioactivity in blood was quite similar for the two routes of administration, with an apparent half-life of approximately 30 h. At 120 to 144 h, a second, slower elimination phase began that was not fully characterized in the 168-h duration of the study. The HPLC analysis of plasma samples revealed intact AL01576 as the only compound in plasma. The mean plasma parent and radioactivity concentrations are in agreement; suggesting the absence of or an insignificant amount of metabolite in the plasma. The urinary and fecal excretion rate data showed a kinetic pattern similar to that of blood radioactivity. Fecal excretion was the primary route of elimination following both intravenous and oral dosing, accounting for 59% of the administered intravenous dose and 61% of the oral dose. Urinary excretion accounted for 32% of the intravenous dose and 29% of the oral dose. Negligible amounts of radioactivity were recovered as expired 14CO2. Experiments with bile-duct cannulated rats confirmed that the major route of elimination of the drug is biliary excretion. The pattern of distribution of [14C] AL01576 in tissues was quite similar following the two routes of administration. Tissue radioactivity concentration peaked at 4 h (the first sampling time) following both routes of administration in all tissues except the GI tract.(ABSTRACT TRUNCATED AT 250 WORDS)
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D005449:Fluorenes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006827:Hydantoins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution
D005449:Fluorenes; D006827:Hydantoins; C052241:imirestat; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase