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Tolrestat kinetics.

D R Hicks, M Kraml, M N Cayen

    Clinical Pharmacology and Therapeutics
    |October 1, 1984
    PubMed
    Summary
    This summary is machine-generated.

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    Tolrestat, an aldose reductase inhibitor, is rapidly absorbed and eliminated in both healthy individuals and those with diabetes. Its pharmacokinetics are dose-independent and show no significant drug interactions.

    Area of Science:

    • Pharmacology
    • Biochemistry

    Background:

    • Aldose reductase inhibitors are investigated for potential therapeutic applications.
    • Understanding the pharmacokinetic profile of tolrestat is crucial for its clinical evaluation.

    Purpose of the Study:

    • To characterize the absorption, distribution, metabolism, and excretion (ADME) of tolrestat.
    • To assess the pharmacokinetics of tolrestat in healthy subjects and subjects with diabetes mellitus.
    • To evaluate the dose-dependency and potential drug interactions of tolrestat.

    Main Methods:

    • Administration of 14C-labeled tolrestat to normal subjects and subjects with diabetes.
    • Measurement of serum concentrations of tolrestat and total radioactivity (14C).
    • Analysis of urinary and fecal excretion of radioactivity.

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    Main Results:

    • Tolrestat exhibited rapid absorption and biphasic elimination from serum, with distribution and elimination half-lives of approximately 2 hours and 10-12 hours, respectively.
    • Unchanged tolrestat constituted the majority of serum radioactivity, indicating minimal metabolism.
    • Radioactivity was rapidly and completely excreted in urine and feces (2:1 ratio), with similar patterns observed in both healthy and diabetic subjects.
    • Pharmacokinetics were dose-independent across a 10-800 mg range in normal subjects.
    • No significant accumulation occurred with repetitive dosing.
    • Tolrestat showed high protein binding (>99%) but did not compete with warfarin; it was displaced by high concentrations of tolbutamide or salicylate.

    Conclusions:

    • Tolrestat demonstrates predictable pharmacokinetics in both healthy and diabetic individuals.
    • The drug's elimination pathway is primarily renal and fecal excretion.
    • Dose-independent kinetics and limited drug-drug interactions suggest a favorable pharmacokinetic profile for tolrestat.