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Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
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Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes

Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases that play a pivotal role in Phase I drug metabolism by catalyzing oxidation and reduction reactions.These enzymes transform lipophilic xenobiotics into more hydrophilic metabolites, facilitating subsequent Phase II conjugation and eventual excretion. The CYP450 family is classified into families (e.g., CYP1–CYP3) and subfamilies (e.g., CYP2A, CYP2C), based on amino acid sequence homology.CYP450 isoenzymes,...
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Phase II biotransformation reactions are essential for detoxifying and eliminating xenobiotics, including many pharmaceutical compounds. These reactions typically involve conjugation, the covalent attachment of polar endogenous groups such as glucuronic acid, sulfate, methyl, or acetyl moieties to functional groups introduced during Phase I metabolism. The resulting conjugates are more water-soluble, enabling efficient renal or biliary excretion.The major classes of Phase II enzymes include...
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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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A Microscopic Phenotypic Assay for the Quantification of Intracellular Mycobacteria Adapted for High-throughput/High-content Screening
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Population screening for isoniazid acetylator phenotype.

H I Seifart1, D P Parkin, F J Botha

  • 1Department of Pharmacology, University of Stellenbosch, Republic of South Africa.

Pharmacoepidemiology and Drug Safety
|August 14, 2001
PubMed
Summary

This study developed a simple method to determine isoniazid acetylator phenotypes using a single blood sample. This aids in personalized tuberculosis treatment by identifying fast, intermediate, and slow acetylators.

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Area of Science:

  • Pharmacogenomics
  • Clinical Chemistry

Background:

  • Isoniazid is a cornerstone medication for tuberculosis treatment.
  • Individual variability in isoniazid metabolism affects treatment efficacy and toxicity.
  • Accurate phenotypification is crucial for optimizing isoniazid therapy.

Purpose of the Study:

  • To develop a practical method for isoniazid acetylator phenotyping.
  • To enable therapeutic drug monitoring of isoniazid.
  • To assess the reliability of a simplified phenotypification assay.

Main Methods:

  • Sixty tuberculosis patients received an oral isoniazid dose.
  • Plasma isoniazid and acetyl-isoniazid concentrations were measured using HPLC.
  • Metabolic ratios were calculated to assess phenotypification methods.

Main Results:

  • A trimodal distribution of metabolic ratios at 3 hours post-dose identified fast, intermediate, and slow acetylator phenotypes.
  • Simplified phenotypification using direct HPLC data without absolute concentrations was feasible.
  • The 2-h and 6-h data also showed distinct bimodal combinations of phenotypes.

Conclusions:

  • A single-sample test combining plasma isoniazid concentration and metabolic ratio is reliable for phenotype discrimination.
  • This method can be used for bioavailability testing.
  • The findings support personalized dosing strategies for isoniazid therapy.