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 phenotypes⁴.

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) are primary treatment options for major depressive and anxiety disorders. It is estimated that 50% of the patients diagnosed with major depressive disorder will fail initial SSRI therapy⁵. An estimated 25,000 patients per year in the US will seek treatment in emergency departments due to adverse events associated with antidepressants⁶. 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 events and treatment failures. CPIC provides dosing guidelines for fluvoxamine, paroxetine, citalopram, escitalopram, and sertraline based on CYP2D6 and/or CYP2C19 genotypes⁷.

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.⁸

Proton pump inhibitors (PPIs)

Proton pump inhibitors are widely used for acid suppression in the treatment of many conditions, such as gastroesophageal reflux disease (GERD), gastric and duodenal ulcers, erosive esophagitis, eosinophilic esophagitis. Long term use of PPIs may pose high risk of adverse events, including electrolyte imbalance (e.g. hypomagnesemia), infections, kidney disease and bone fractures⁹. The PPIs are metabolized into inactive form primarily by CYP2C19 enzyme. CYP2C19 genetic variants have been linked to PPI exposures. Lower exposure may lead to treatment failure and higher exposure has also been associated with adverse effects. CYP2C19 is a major metabolic pathway for the clearance (~80%) of first-generation PPIs, including omeprazole, lansoprazole, and pantoprazole. The second-generation PPIs, including esomeprazole, rabeprazole and dexlansoprazole, appear to be less influenced by CYP2C19 genetic variations, compared to first-generation PPIs¹⁰. Using the pharmacogenetic information of CYP2C19 to guide PPI therapy has the potential to improve efficacy and reduce risk of toxicity associated with long term use, particularly at high plasma concentration¹¹.

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