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.
Footnotes
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Send reprint requests to: Dr. Philip B. Inskeep, Animal Health Central Research, Safety and Metabolism, Pfizer Inc., Groton, CT 06340.
- Abbreviations used are::
- ACN
- acetonitrile
- LSA
- liquid scintillation analysis
- MRM
- multiple reaction monitoring
- β-RAM
- β-radioactivity monitor
- NH4OAc
- ammonium acetate
- kel
- elimination rate constant
- Tmax
- time of the first occurrence of the maximal plasma concentration
- Cmax
- maximal plasma concentration
- Received February 4, 1998.
- Accepted June 18, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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