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Interpatient variability: genetic predisposition and other genetic factors
W L West1, E M Knight, S Pradhan
1Center for Drug Abuse Research (CDAR), Howard University, Department of Pharmacology/Center for Drug Abuse Research, College of Medicine, Howard University, Washington, DC 20059, USA.
Journal of Clinical Pharmacology
|July 1, 1997
Summary
Genetic variations in drug-metabolizing enzymes, like cytochromes P-450 (CYP) and glutathione-s-transferases, impact drug efficacy. Understanding these genetic polymorphisms is crucial for personalized medicine and predicting patient responses.
Area of Science:
- Pharmacogenomics
- Enzymology
- Molecular Biology
Background:
- Genetic factors significantly influence drug and xenobiotic metabolism.
- Interpatient variability in enzyme expression affects drug response.
- Polymorphisms in key metabolic enzymes are well-documented.
Purpose of the Study:
- To explore molecular mechanisms of genetic polymorphisms in drug-metabolizing enzymes.
- To highlight clinical implications of genetically determined enzyme variability.
- To provide examples of Phase I and Phase II polymorphic enzymes.
Main Methods:
- Focus on selected polymorphic enzymes: cytochromes P-450 (CYP) for Phase I.
- Examination of methyl transferases, n-acetyl transferases, and glutathione-s-transferases for Phase II.
- Brief description of arylhydrocarbon hydroxylase induction polymorphism.
Main Results:
- Phase I reactions are primarily oxidative; Phase II reactions often conjugate Phase I byproducts.
- Poor metabolizers exhibit limited drug metabolism, especially for prodrugs.
- Clinical significance is linked to substrate, metabolite, and elimination pathways.
Conclusions:
- Genetic polymorphisms in drug-metabolizing enzymes are clinically significant.
- Variability in enzyme activity impacts drug efficacy and safety.
- Understanding these genetic factors is essential for optimizing pharmacotherapy.