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 | R P Schneider, C J Davenport, K A Hoffmaster, P B Inskeep |
Journal | Drug metabolism and disposition: the biological fate of chemicals
(Drug Metab Dispos)
Vol. 26
Issue 11
Pg. 1160-6
(Nov 1998)
ISSN: 0090-9556 [Print] United States |
PMID | 9806960
(Publication Type: Journal Article)
|
Chemical References |
- Benzothiazoles
- Enzyme Inhibitors
- Hypoglycemic Agents
- Phthalazines
- Thiazoles
- zopolrestat
- Aldehyde Reductase
|
Topics |
- Administration, Oral
- Aldehyde Reductase
(antagonists & inhibitors)
- Animals
- Benzothiazoles
- Biological Availability
- Biotransformation
- Dogs
- Drug Administration Schedule
- Enzyme Inhibitors
(blood, pharmacokinetics, urine)
- Female
- Half-Life
- Hypoglycemic Agents
(blood, pharmacokinetics, urine)
- Male
- Mass Spectrometry
- Phthalazines
(blood, pharmacokinetics, urine)
- Thiazoles
(blood, pharmacokinetics, urine)
|