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Research ArticleArticle

Bioavailability, Multiple-Dose Pharmacokinetics, and Biotransformation of the Aldose Reductase Inhibitor Zopolrestat in Dogs

Richard P. Schneider, Cynthia J. Davenport, Keith A. Hoffmaster and Philip B. Inskeep
Drug Metabolism and Disposition November 1998, 26 (11) 1160-1166;
Richard P. Schneider
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Cynthia J. Davenport
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Keith A. Hoffmaster
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Philip B. Inskeep
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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

  • 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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Drug Metabolism and Disposition
Vol. 26, Issue 11
1 Nov 1998
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Research ArticleArticle

Bioavailability, Multiple-Dose Pharmacokinetics, and Biotransformation of the Aldose Reductase Inhibitor Zopolrestat in Dogs

Richard P. Schneider, Cynthia J. Davenport, Keith A. Hoffmaster and Philip B. Inskeep
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1160-1166;

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Research ArticleArticle

Bioavailability, Multiple-Dose Pharmacokinetics, and Biotransformation of the Aldose Reductase Inhibitor Zopolrestat in Dogs

Richard P. Schneider, Cynthia J. Davenport, Keith A. Hoffmaster and Philip B. Inskeep
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1160-1166;
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