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Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

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...
Pharmacogenetics of Phase I Enzymes: Cytochrome P450 Isozymes01:28

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...
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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Pharmacogenetics of Drug Metabolism: Overview

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...
Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow01:26

Effect of Hepatic Disease on Pharmacokinetics: Drug Dosing and Hepatic Blood Flow

Chronic liver disease significantly impacts drug metabolism due to alterations in hepatic blood flow and enzyme accessibility. This disruption affects the body's pharmacokinetics—the movement and processing of drugs within the system. Key enzymes crucial for metabolizing medications become less accessible, changing how drugs are processed and utilized. Furthermore, liver disease influences the synthesis of plasma proteins, such as albumin and globulins, which play critical roles in drug binding...

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Multi-Gene Single Nucleotide Polymorphism Detection in Gastric Cancer Based on Ion Semiconductor Sequencing Platform
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Do 5-fluorouracil therapies alter CYP2C19 metaboliser status?

N A Helsby1, W Y Lo, P Thompson

  • 1Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand. n.helsby@auckland.ac.nz

Cancer Chemotherapy and Pharmacology
|February 18, 2010
PubMed
Summary

5-fluorouracil (FU) treatment altered a patient's CYP2C19 metaboliser status, leading to decreased enzyme activity and a shift from extensive to poor metaboliser. This change coincided with the development of hand and foot syndrome.

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Mass Spectrometry and Luminogenic-based Approaches to Characterize Phase I Metabolic Competency of In Vitro Cell Cultures
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Area of Science:

  • Pharmacogenomics
  • Drug Metabolism
  • Oncology

Background:

  • Colorectal cancer treatment often involves 5-fluorouracil (FU/FA).
  • Individual variability in drug metabolism influences treatment efficacy and toxicity.
  • Cytochrome P450 enzymes, including CYP2C19, play a crucial role in drug metabolism.

Observation:

  • A patient with colorectal adenocarcinoma received 5-fluorouracil and folinic acid (FU/FA).
  • CYP2C19 genotype and activity were assessed using proguanil as a probe substrate.
  • The patient's CYP2C19 activity decreased significantly during FU/FA treatment, altering their metaboliser status.

Findings:

  • The patient, initially an extensive CYP2C19 metaboliser (CYP2C19*1/*1), became a poor metaboliser during FU/FA therapy.
  • This metabolic shift occurred between day 7 and day 21 of testing.
  • Grade III hand and foot syndrome developed during the period of reduced CYP2C19 activity.

Implications:

  • 5-fluorouracil (FU) may inhibit CYP2C19 synthesis, impacting drug metabolism.
  • Altered CYP2C19 activity could influence the clinical outcomes of drugs metabolized by this enzyme, such as warfarin and phenytoin.
  • This case highlights the potential for chemotherapy to affect pharmacogenetic profiles and drug disposition.