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Polymorphic drug oxidation in humans.

M Eichelbaum

    Federation Proceedings
    |May 15, 1984
    PubMed
    Summary
    This summary is machine-generated.

    Genetic variations affect drug metabolism, leading to poor metabolizer (PM) phenotypes with impaired drug processing. This can cause adverse effects and treatment failure in individuals with specific genetic polymorphisms.

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    Area of Science:

    • Pharmacogenetics
    • Drug Metabolism
    • Human Genetics

    Background:

    • Genetic polymorphisms influence the oxidative metabolism of various drugs.
    • Polymorphic oxidation of debrisoquine and sparteine is well-studied, revealing two phenotypes: extensive metabolizers (EM) and poor metabolizers (PM).
    • PM individuals exhibit significantly reduced capacity to metabolize specific drugs.

    Purpose of the Study:

    • To investigate the implications of genetic polymorphisms in drug metabolism.
    • To characterize the poor metabolizer (PM) phenotype and its impact on drug efficacy and safety.
    • To explore the molecular basis of impaired drug metabolism in PM individuals.

    Main Methods:

    • Phenotyping studies using debrisoquine and sparteine.
    • Population genetic analysis to determine the incidence of PM phenotype across ethnic groups.

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  • In vitro studies using human liver microsomes to investigate enzyme activity.

    • Main Results:

    • The PM phenotype, characterized by impaired drug metabolism, occurs in 5-9% of European populations, with variations across ethnic groups.
    • PM individuals are homozygous for an autosomal recessive gene affecting drug metabolism.
    • Impaired metabolism is not limited to debrisoquine and sparteine, affecting other drugs like phenformin and metoprolol, leading to toxicity and therapeutic failure.

    Conclusions:

    • Genetic polymorphisms significantly impact drug metabolism, defining distinct phenotypes like PM.
    • The PM phenotype is associated with increased risk of adverse drug reactions and treatment failure.
    • A deficiency or functional inadequacy of a specific cytochrome P-450 isozyme is implicated in the PM phenotype.