title: Bioavailability, multiple-dose pharmacokinetics, and biotransformation of the aldose reductase inhibitor zopolrestat in dogs.
abstract: 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.
authors.affiliation: Drug Metabolism Department, Central Research Division, Pfizer Inc., Groton, CT 06340, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Schneider
authors.forename: C J
authors.initials: CJ
authors.lastname: Davenport
authors.forename: K A
authors.initials: KA
authors.lastname: Hoffmaster
authors.forename: P B
authors.initials: PB
authors.lastname: Inskeep
mesh_terms: D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D052160:Benzothiazoles; D001682:Biological Availability; D001711:Biotransformation; D004285:Dogs; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005260:Female; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008297:Male; D013058:Mass Spectrometry; D010793:Phthalazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013844:Thiazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010793:Phthalazines; D013844:Thiazoles; C067172:zopolrestat; D000449:Aldehyde Reductase