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Research ArticleArticle

Tissue Distribution and Biotransformation of Zopolrestat, an Aldose Reductase Inhibitor, in Rats

Richard P. Schneider, Hassan G. Fouda and Philip B. Inskeep
Drug Metabolism and Disposition November 1998, 26 (11) 1149-1159;
Richard P. Schneider
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Hassan G. Fouda
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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.14C-labeled zopolrestat was orally administered to rats for a tissue distribution study and a bile duct cannulation metabolism study. Tissue samples from the distribution study were analyzed by complete oxidation and liquid scintillation counting. Urine and bile samples from the bile duct cannulation study were analyzed by microbore HPLC, with simultaneous radioactivity monitoring and atmospheric pressure ionization tandem mass spectrometry. The mass balance in the distribution study demonstrated that the greatest exposure (AUC0–∞) occurred in the liver, followed by the ileum and large intestine. The time of maximal plasma concentrations for nearly all tissues was 4 hr after the dose, and the half-life of radioactivity in most tissues (8–10 hr) was similar to the half-life in plasma. For the bile duct-cannulated rat study, most of the radioactivity was recovered in the bile, indicating that biliary excretion is a major route of elimination of zopolrestat and its metabolites in rats. Numerous oxidative metabolites, as well as phase II conjugates, were identified in the bile and urine samples. Acyl glucuronides of zopolrestat and unchanged drug accounted for >85% of biliary radioactivity, whereas unchanged drug and degradation products of glutathione conjugates were identified as the major urinary metabolites.

Footnotes

  • Send reprint requests to: Richard Schneider, Department of Drug Metabolism, Central Research Division, Pfizer Inc., Groton, CT 06340.

  • Abbreviations used are::
    LSA
    liquid scintillation analysis
    CID
    collisioninduced dissociation
    ACN
    acetonitrile
    NH4OAc
    ammonium acetate
    β-RAM
    β-radioactivity monitor
    NAC
    N-acetylcysteine
    Cmax
    maximal plasma concentration
    GSH
    glutathione
    • 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

Tissue Distribution and Biotransformation of Zopolrestat, an Aldose Reductase Inhibitor, in Rats

Richard P. Schneider, Hassan G. Fouda and Philip B. Inskeep
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1149-1159;

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Research ArticleArticle

Tissue Distribution and Biotransformation of Zopolrestat, an Aldose Reductase Inhibitor, in Rats

Richard P. Schneider, Hassan G. Fouda and Philip B. Inskeep
Drug Metabolism and Disposition November 1, 1998, 26 (11) 1149-1159;
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