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Related Concept Videos

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

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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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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...
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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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Idiosyncratic drug reactions represent abnormal chemical responses that vary significantly among individuals, ranging from extreme sensitivity to low doses to insensitivity to high doses. These reactions often occur due to the drug's covalent binding with serum proteins, forming a foreign hapten that triggers an immunotoxicological response. The variability in drug reactions has a strong pharmacogenetic foundation, with genetic differences crucial in how individuals metabolize drugs. For...
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Hepatic impairment, characterized by decreased liver function, does not uniformly mandate adjustments in drug dosage. Whether dosage modifications are necessary depends on various factors related to the drug's metabolism and elimination pathways. If a drug is primarily excreted via the kidneys and bypasses significant hepatic processing, if it undergoes minimal metabolic transformation in the liver, or if it is volatile and primarily expelled through the lungs, dose adjustments may not be...
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The empirical approach to drug therapy optimization relies on correlating pharmacological response with administered dosage. Such an approach can be costly, time-consuming, and often yields poor correlation due to variables like formulation factors and drug elimination characteristics. A more precise approach correlates response with plasma drug concentration or the amount of drug in the body, rather than dosage. This is achieved through pharmacokinetic-pharmacodynamic (PK/PD) modeling, which...
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Related Experiment Video

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Optimizing clopidogrel dose response: a new clinical algorithm comprising CYP2C19 pharmacogenetics and drug

Yolande B Saab1, Rony Zeenny2, Wijdan H Ramadan2

  • 1School of Pharmacy, Pharmaceutical Sciences Department, Lebanese American University, Byblos, Lebanon.

Therapeutics and Clinical Risk Management
|October 8, 2015
PubMed
Summary

Clopidogrel response varies due to CYP2C19 gene variants and drug interactions. A new algorithm personalizes clopidogrel dosing to improve treatment efficacy and reduce adverse effects.

Keywords:
genetic testinggenotypeindividualized therapypharmacogenetics

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Area of Science:

  • Pharmacogenomics
  • Clinical Pharmacology
  • Internal Medicine

Background:

  • Clopidogrel response exhibits significant inter-individual variability, with nonresponse rates from 4% to 30%.
  • CYP2C19 gene variants and drug interactions are known to affect clopidogrel metabolism and efficacy.
  • Reduced CYP2C19 function leads to lower drug metabolite levels and diminished platelet inhibition.

Purpose of the Study:

  • To investigate the cumulative impact of CYP2C19 polymorphisms and drug interactions on clopidogrel dosing.
  • To develop a novel clinical-pharmacogenetic algorithm for optimizing clopidogrel treatment.

Main Methods:

  • Analyzed clopidogrel dose optimization based on CYP2C19 genotypes and concomitant drug intake.
  • Calculated adjusted clopidogrel doses using area under the curve ratios for different genotypes with interacting drugs.
  • Developed a clinical-pharmacogenetic algorithm based on expected effect, lack of effect, or adverse drug reactions.

Main Results:

  • Patients with non-*1*1 CYP2C19 genotypes and taking interacting drugs require clopidogrel dose adjustments.
  • Dose adjustments can range from 6 mg to 215 mg for a standard 75 mg clopidogrel dose to achieve therapeutic effect and avoid toxicity.

Conclusions:

  • The developed algorithm can personalize clopidogrel therapy to maximize pharmacological benefits.
  • Implementation of this algorithm allows clinicians to enhance treatment efficacy and limit toxicity.