PT  - JOURNAL ARTICLE
AU  - Richard P. Schneider
AU  - Cynthia J. Davenport
AU  - Keith A. Hoffmaster
AU  - Philip B. Inskeep
TI  - Bioavailability, Multiple-Dose Pharmacokinetics, and Biotransformation of the Aldose Reductase Inhibitor Zopolrestat in Dogs
DP  - 1998 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1160--1166
VI  - 26
IP  - 11
4099  - http://dmd.aspetjournals.org/content/26/11/1160.short
4100  - http://dmd.aspetjournals.org/content/26/11/1160.full
SO  - Drug Metab Dispos1998 Nov 01; 26
AB  - Zopolrestat (Alond) is a new drug that is being evaluated as an aldose reductase inhibitor for the treatment of diabetic complications. The bioavailability in dogs of a 2 mg/kg oral dose of zopolrestat was 97.2%. In a 1-year, multiple-dose, pharmacokinetic study, systemic exposure increased with increasing dose (50, 100, and 200 mg/kg/day), and there were no consistent changes in exposure with multiple dosing. Renal clearance at 1 year appeared to be higher in males. The magnitude of the potential gender difference in exposure was relatively small and was unlikely to have had a meaningful impact on the pharmacokinetics of zopolrestat in dogs. In studies with bile duct-cannulated dogs, radioactivity from [14C]zopolrestat was primarily eliminated as unchanged drug and acyl glucuronide in the bile and feces (77.3% of the dose) and in urine (18.3% of the dose). The concentrations of acyl glucuronide in urine and feces were approximately 50% of the zopolrestat concentrations. Minor metabolites (each accounting for <1% of the dose) included those resulting from hydroxylation of the phthalazinone ring and glutathione conjugation of the benzothiazole ring. The American Society for Pharmacology and Experimental Therapeutics