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Drug toxicity: Idiosyncratic Reactions01:16

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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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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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Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

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The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
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Pharmacogenetics of Drug Metabolism: Overview01:27

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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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Drug Toxicity: Risk factors01:24

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Adverse Drug Reactions (ADRs) are potential complications that arise during pharmacotherapy, influenced by multiple risk factors. Age plays a significant role; both neonates and the elderly are at heightened risk due to their respective immature and diminished metabolic and elimination processes. Gender also impacts ADRs, with females experiencing a 1.5 to 1.7-fold greater risk than males, which may be linked to pharmacokinetic, pharmacodynamic, and hormonal differences. Notably, neonates, the...
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The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
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ABCG2 Genetic Variability in Drug Exposure and Toxicity: Implications for Clinical Practice.

Tamara Božina1, Livija Šimičević1,2, Lana Ganoci2,3

  • 1Department for Chemistry and Biochemistry, University of Zagreb School of Medicine, Šalata 3, 10000 Zagreb, Croatia.

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Summary

Genetic variations in the ABCG2 transporter protein impact drug efficacy and toxicity. Understanding these genetic differences, particularly the ABCG2 c.421C>A variant, can help personalize drug therapy and improve patient outcomes.

Keywords:
ABCG2 proteinATP-binding cassette transportersdrug interactionsdrug transportersdrug-related side effects and adverse reactionspharmacogeneticspolygenic risk scoreprecision medicine

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Area of Science:

  • Pharmacogenomics
  • Molecular Biology
  • Drug Metabolism

Background:

  • ABCG2 (BCRP) is a crucial efflux transporter influencing drug exposure.
  • Genetic variants in ABCG2 contribute significantly to interindividual differences in drug response.
  • ABCG2 genetic variability affects drug efficacy and toxicity.

Purpose of the Study:

  • To review the clinical relevance of ABCG2 genetic variants.
  • To focus on effects on pharmacokinetics, adverse drug reactions, and drug-drug-gene interactions.
  • To explore the potential of ABCG2 genotyping in personalized therapy.

Main Methods:

  • Narrative review of literature.
  • Searches conducted in PubMed, Scopus, and ClinPGx.
  • Emphasis on clinically relevant studies and pharmacogenomic guidelines.

Main Results:

  • The ABCG2 c.421C>A variant (rs2231142) reduces transporter activity.
  • This variant increases systemic exposure to drugs like statins, allopurinol, and anticancer agents.
  • Reduced activity influences treatment response and toxicity risk.

Conclusions:

  • Growing evidence supports the clinical relevance of ABCG2 genotyping.
  • Routine implementation of ABCG2 genotyping is currently limited.
  • Integrating ABCG2 variability into clinical tools can enhance personalized medicine, especially for patients with multiple conditions and medications.