Disposition of the Aldose Reductase Inhibitor AL01576 in Rats

Abstract

The disposition of the aldose reductase inhibitor AL01576 was studied in rats following intravenous and oral dosing. Single 4mg/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 ~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 Gl tract. The highest radioactivity concentrations at 4 and 24 h were in the Gl tract, kidney, adrenals, and liver. At 168 h, the highest concentrations of radioactivity were found in the testes, kidneys, lungs, and adrenals, although the recovery from these four tissues combined represented <0.5% of the administered dose. After intravenous dosing, the recovery of radioactivity in the selected tissues (blood, liver, kidney, lung, brain, heart, spleen, testes, muscle, eyes, adrenals, skin, fat, and Gl tract) measured was 82, 75, 13, and 4% of the administered dose at 4, 24, 72, and 168 h, respectively. Overall, the data suggest that AL01576 is readily absorbed when administered orally, is distributed throughout the body tissues, is excreted predominantly by the feces through biliary excretion, and has a low systemic clearance and a long biologic half-life.