Disposition of the aldose reductase inhibitor AL01576 in rats

• Published in: Journal of pharmaceutical sciences Vol. 77; no. 2; p. 110
• Main Authors: Park, Y H, Wooldridge, C B, Mattern, J, Stoltz, M L, Brazzell, R K
• Format: Journal Article
• Language: English
• Published: United States 01-02-1988
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Animals; Fluorenes - administration & dosage; Fluorenes - blood; Fluorenes - pharmacokinetics; Hydantoins - administration & dosage; Hydantoins - blood; Hydantoins - pharmacokinetics; Male; Rats; Rats, Inbred Strains; Sugar Alcohol Dehydrogenases - antagonists & inhibitors; Tissue Distribution
• ISSN: 0022-3549
• DOI: 10.1002/jps.2600770204

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.