Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism

  title={Clinical Significance of the Cytochrome P450 2C19 Genetic Polymorphism},
  author={Zeruesenay Desta and Xiaojiong Zhao and Jae-Gook Shin and David A. Flockhart},
  journal={Clinical Pharmacokinetics},
Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that pre-diet PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic… 
CYP2C19 and CYP2C9 : New aspects of pharmacogenetics and transcriptional regulation
Novel mechanisms are established of CYP2C9 and CYP 2C19 transcriptional regulation that involve transcription factors from the GATA family and estrogen receptor α and the estrogen mediated regulation may explain the clinically observed inhibitory effects of oral contraceptives.
Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals
The frequency of poor metabolizers in the Colombian mestizos included in this study is similar to that in Bolivian mestIZos but lower than in Mexican-Americans, West Mexicans, Caucasians and African Americans.
Results support the use of rosiglitazone as an in vivo probe of CYP2C8 activity, as it is affected by CYP 2C8 inhibitors and inducers.
Applications of CYP450 Testing in the Clinical Setting
The relevant data on the clinical impact of the major CYP polymorphisms on drug therapy where genotyping and phenotyping may be considered, and the guidelines developed when available are presented, are presented.
CYP2C19 pharmacogenetics in advanced cancer: compromised function independent of genotype
It is indicated that in a cancer population genotyping for CYP2C19 would significantly underestimate the number of phenotypic PM of drugs, such as cyclophosphamide, which may be metabolised by this enzyme.
Polymorphism of human cytochrome P450 enzymes and its clinical impact
Current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) is highlighted to understand the large interindividual variability in drug clearance and responses in clinical practice and to improve the efficacy and safety of both prospective and currently available drugs.
Effects of CYP2C19 variants on methadone metabolism in vitro.
Findings suggest that more attention should be paid in clinical administration of methadone to individuals carrying these CYP2C19 alleles, which might cause undesirable adverse effects or cure failure at standard dosages.
Genetic polymorphism of CYP2C19 & therapeutic response to proton pump inhibitors.
Proton pump inhibitors (PPIs) are extensively metabolized in the liver by CYP2C19, that demonstrates genetic polymorphism with 21 mutant alleles. The subjects can be divided into 2 groups with
Genetic Polymorphism of Drug-Metabolizing Enzymes CYP2C9 and CYP2C19 in Moroccan Population.
The results suggest that only CYP 2C9*2 and CYP2C19*2 are likely to substantially contribute to individual and interethnic variability of CY2C9-19 activity in the Moroccan population.
The Role of Pharmacogenetics in the Metabolism of Antiepileptic Drugs
  • U. Klotz
  • Biology, Medicine
    Clinical pharmacokinetics
  • 2007
The traditional and validated therapeutic drug monitoring approach, representing a direct ‘phenotype’ assessment, still remains the method of choice when an individualised dosing regimen is anticipated, but pharmacogenetics and pharmacogenomics can offer some novel contributions when attempts are made to maximise drug efficacy and enhance drug safety.


Cytochrome P4502C9: an enzyme of major importance in human drug metabolism.
Consistent with the modulation of enzyme activity by genetic and other factors, wide interindividual variability occurs in the elimination and/or dosage requirements of prototypic CYP2C9 substrates.
Biochemistry and molecular biology of the human CYP2C subfamily.
A well-characterized genetic polymorphism occurs in the 2C subfamily which is associated with the metabolism of the anticonvulsant drug mephenytoin, and the availability of genotyping tests for this polymorphism will enhance the assessment of the role of this pathway in clinical studies.
Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A
Inhibition of one or both CYP2C19 and CYP3A isoforms is the likely mechanism by which INH slows the elimination of coadministered drugs, including phenytoin, carbamazepine, diazepam, triazolam, and primidone.
Geographical/Interracial Differences in Polymorphic Drug Oxidation
Diazepam is partially demethylated by CYP2C19, and the high frequency of mutated alleles in Orientals is probably the reason why such populations have a slower metabolism and are treated with lower doses of diazepam than Caucasians.
Genetic polymorphism of S-mephenytoin 4'-hydroxylation.
Genotyping an individual before treatment with substrates of CYP2C19 will reduce the risk of side effects and improve compliance in PMs, which is relatively low in African-Americans and Caucasians and as high as 20 percent in Asian populations.
Cytochrome P450 Isozymes and Antiepileptic Drug Interactions
  • R. Levy
  • Biology, Chemistry
  • 1995
Summary: Recent findings about individual isoforms of the cytochromes P450 involved in the metabolism of phe‐nytoin (PHT) and carbamazepine (CBZ) make prediction of inhibition‐based interactions
Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin.
Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations, and a significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes.
Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation.
Wild type CYP 2C19 and CYP2C9 are relatively low Km catalysts of cyclophosphamide and ifosfamide activation, and all four human CYP1C enzymes activate these two anticancer prodrugs with varying efficiencies and with striking differences among naturally occurring allelic variants.
CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system.
Findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity, however, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodILine.