Gene Description

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Gene Description

CYP2C19

The cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) gene is predominantly expressed in the liver. The hepatic CYP2C19 enzyme contributes to the metabolism of many drugs such as antidepressants, benzodiazepines, mephenytoin, some proton pump inhibitors, and clopidogrel.1

Clopidogrel

Clopidogrel is a commonly prescribed antiplatelet prodrug that is metabolized into an active form by several hepatic CYP450 enzymes, predominantly CYP2C19. The active metabolite inhibits ADP-mediated platelet activation and aggregation.2 Clopidogrel is commonly prescribed for acute coronary syndromes (ACSs) and/or following percutaneous coronary intervention (PCI). The CYP2C19 loss-of-function alleles impair formation of active metabolites, and therefore result in reduce platelet inhibition. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommends the alternative antiplatelet therapy, such as prasugrel and ticagrelor, for the intermediate or poor metabolizer based on the CYP2C19 genotype. Label-instructed dosage and administration is recommended for the ultrarapid metabolizer (UM) and extensive metabolizer (EM).3

Voriconazole

Voriconazole is an antifungal agent approved for the treatment of various diseases and infections, such as invasive aspergillosis, candidemia in non-neutropenic patients, disseminated Candida infections. Voriconazole is metabolized predominantly by CYP2C19, as well as CYP3A and CYP2C9. A wide interpatient variability observed in the pharmacokinetics of voriconazole is partly due to the spectrum of CYP2C19 alleles. The CPIC guideline provides dosing recommendations for the drug based on the CYP2C19 phenotypes.

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. Polymorphisms on CYP2C19 as well as on CYP2D6 can influence the metabolism of SSRIs, and thereby affect drug efficacy and safety. Utilizing pharmacogenetics results to guide SSRI therapy could potentially improve the treatment responses and reduce the occurrence of adverse events5 and or treatment failures.

Tricyclic antidepressants (TCAs)

Tricyclic antidepressants (TCAs), including imipramine, amitriptyline, trimipramine and clomipramine, and of the secondary amine TCA nortriptyline, are used to treat several disease states including depression, obsessive-compulsive disorder, and neuropathic pain in addition to migraine prophylaxis. There is substantial evidence linking CYP2C19 and CYP2D6 genotypes to the interpatient variability in TCA side effects and pharmacokinetic profiles. Using the pharmacogenetic information of the two genes to guide TCA dosing and selection could potentially improve clinical outcome and reduce adverse events.6

 

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References
  1. Scott SA, et al. PharmGKB Summary: Very Important Pharmacogene Information for Cytochrome P450, Family 2, Subfamily C, Polypeptide 19. Pharmacogenet Genom. 2012.
  2. Sangkuhl K, et al. Clopidogrel Pathway. Pharmacogenet Genom. 2010.
  3. Scott SA, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-23.
  4. Moriyama B, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2017;102(1):45-51.
  5. Hicks JK, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-34.
  6. Hicks JK, et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 update. Clin Pharmacol Ther. 2017 Jul;102(1):37-44.