RT Journal Article
SR Electronic
T1 Bioavailability, Multiple-Dose Pharmacokinetics, and Biotransformation of the Aldose Reductase Inhibitor Zopolrestat in Dogs
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1160
OP 1166
VO 26
IS 11
A1 Richard P. Schneider
A1 Cynthia J. Davenport
A1 Keith A. Hoffmaster
A1 Philip B. Inskeep
YR 1998
UL http://dmd.aspetjournals.org/content/26/11/1160.abstract
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