Review
Impact of Genetic Polymorphisms in CYP2C9 and CYP2C19 on the Pharmacokinetics of Clinically Used Drugs

https://doi.org/10.2133/dmpk.DMPK-12-RV-085Get rights and content

Summary:

Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug-metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty-two allelic variants for CYP2C9 and 34 for CYP2C19 have been reported. The frequencies of these variants show marked inter-ethnic variation. The functional consequences of genetic polymorphisms have been examined, and many studies have shown the clinical importance of these polymorphisms. Current evidence suggests that taking the genetically determined metabolic capacity of CYP2C9 and CYP2C19 into account has the potential to improve individual risk/benefit relationships. However, more prospective studies with clinical endpoints are needed before the paradigm of "personalized medicine" based on the variants can be established. This review summarizes the currently available important information on this topic.

References (110)

  • Y.L. Liu et al.

    Effect of the CYP2C9*3 allele on lornoxicam metabolism

    Clin. Chim. Acta

    (2006)
  • S. Uchida et al.

    Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes

    Drug Metab. Pharmacokinet.

    (2010)
  • S. Fudio et al.

    Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram

    Eur. J. Pharmacol.

    (2010)
  • J.T. Brandt et al.

    Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel

    J. Thromb. Haemost.

    (2007)
  • T. Aoshima et al.

    Effects of the CYP2C19 genotype and cigarette smoking on the single oral dose pharmacokinetics and pharmacodynamics of estazolam

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2003)
  • S. Rendic

    Summary of information on human CYP enzymes: human P450 metabolism data

    Drug Metab. Rev.

    (2002)
  • W.E. Evans et al.

    Pharmacogenomics: translating functional genomics into rational therapeutics

    Science

    (1999)
  • J.O. Miners et al.

    Cytochrome P4502C9: an enzyme of major importance in human drug metabolism

    Br. J. Clin. Pharmacol.

    (1998)
  • T. Shimada et al.

    Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians

    J. Pharmacol. Exp. Ther.

    (1994)
  • S. Rendic et al.

    Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers, and inhibitors

    Drug Metab. Rev.

    (1997)
  • T.H. Sullivan-Klose et al.

    The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism

    Pharmacogenetics

    (1996)
  • A.E. Rettie et al.

    Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9

    Pharmacogenetics

    (1994)
  • D.J. Steward et al.

    Genetic association between sensitivity to warfarin and expression of CYP2C9*3

    Pharmacogenetics

    (1997)
  • H. Ninomiya et al.

    Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication

    Ther. Drug Monit.

    (2000)
  • J.A. Goldstein et al.

    Biochemistry and molecular biology of the human CYP2C subfamily

    Pharmacogenetics

    (1994)
  • C.L. Crespi et al.

    The R144C change in the CYP2C9*2 allele alters interaction of the cytochrome P450 with NADPH:cytochrome P450 oxidoreductase

    Pharmacogenetics

    (1997)
  • K. Takanashi et al.

    CYP2C9 Ile359 and Leu359 variants: enzyme kinetic study with seven substrates

    Pharmacogenetics

    (2000)
  • J. Imai et al.

    Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus

    Pharmacogenetics

    (2000)
  • A.C. Allabi et al.

    Functional impact of CYP2C9*5, CYP2C9* 6, CYP2C9*8, and CYP2C9*11 in vivo among black Africans

    Clin. Pharmacol. Ther.

    (2004)
  • A.C. Allabi et al.

    CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population

    Pharmacogenet. Genomics

    (2005)
  • L.J. Dickmann et al.

    Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans

    Mol. Pharmacol.

    (2001)
  • R.S. Kidd et al.

    Identification ofa null allele ofCYP2C9 in an African-American exhibiting toxicity to phenytoin

    Pharmacogenetics

    (2001)
  • K. Mamiya et al.

    The effects of genetic polymorphisms of CYP2C9 and CYP2C19 on phenytoin metabolism in Japanese adult patients with epilepsy: studies in stereoselective hydroxylation and population pharmacokinetics

    Epilepsia

    (1998)
  • J. Blaisdell et al.

    Discovery of new potentially defective alleles of human CYP2C9

    Pharmacogenetics

    (2004)
  • D. Si et al.

    Identification of a novel variant CYP2C9 allele in Chinese

    Pharmacogenetics

    (2004)
  • M. Karaźniewicz-łada et al.

    Pharmacokinetic studies of enantiomers of ibuprofen and its chiral metabolites in humans with different variants of genes coding CYP2C8 and CYP2C9 isoenzymes

    Xenobiotica

    (2009)
  • E. Garcia-Martin et al.

    Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms

    Clin. Pharmacol. Ther.

    (2004)
  • E. Yuen et al.

    Ethnic differences in the population pharmacokinetics and pharmacodynamics of warfarin

    J. Pharmacokinet. Pharmacodyn.

    (2010)
  • H. Takahashi et al.

    Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes

    Pharmacogenetics

    (1998)
  • H. Takahashi et al.

    Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes

    Clin. Pharmacol. Ther.

    (1998)
  • C. Martinez et al.

    The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects

    Br J. Clin. Pharmacol.

    (2005)
  • C. Sachse-Seeboth et al.

    Inter-individual variation in the pharmacokinetics of Delta9-tetrahydrocannabinol as related to genetic polymorphisms in CYP2C9

    Clin. Pharmacol. Ther.

    (2009)
  • J. Kirchheiner et al.

    Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (—)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers

    Clin. Pharmacol. Ther.

    (2003)
  • M. Niemi et al.

    Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes

    Clin. Pharmacol. Ther

    (2002)
  • J. Kirchheiner et al.

    Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers

    Clin. Pharmacol. Ther

    (2002)
  • S.V. Vormfelde et al.

    Genetic variation at the CYP2C locus and its association with torsemide biotransformation

    Pharmacogenomics J.

    (2007)
  • J. Kirchheiner et al.

    Influence of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its metabolites

    Pharmacogenetics

    (2003)
  • R. Vianna-Jorge et al.

    CYP2C9 genotypes and the pharmacokinetics of tenoxicam in Brazilians

    Clin. Pharmacol. Ther

    (2004)
  • H.D. Yoo et al.

    Population pharmacokinetic analysis of glimepiride with CYP2C9 genetic polymorphism in healthy Korean subjects

    Eur. J. Clin. Pharmacol.

    (2011)
  • J. Kirchheiner et al.

    The CYP2C9 polymorphism: from enzyme kinetics to clinical dose recommendations

    Personalized Med

    (2004)
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