Cytochrome P450 CYP2C19 is known to preferentially metabolize acidic drugs including proton-pump inhibitors, antidepressants, antiepileptics, and antiplatelet drugs (Chapter 4). Four clinical phenotypes related to CYP2C19 activity (PM, IM, EM, and UM) are closely associated with genetic biomarkers that may assist in guiding individualized therapeutic dosing strategies. The gene that encodes CYP2C19 is highly polymorphic, with over 30 alleles defined (www.cypalleles.ki.se/cyp2c19.htm), yet just four alleles can account for the majority of phenotypic variability, ie, CYP2C19 allele *2 and *3 are nonfunctional, CYP2C19 allele *1 is fully functional, and CYP2C19*17 has increased function. Phenotypes range from PMs who have two deficient alleles, eg, *2/*3, *2/*2, or *3/*3, to UMs who have increased hepatic expression levels of the CYP2C19 protein, due to *1/*17 or *17/*17 alleles (see Table 5–2). Of note, the *17 increased function allele is unable to fully compensate for nonfunctional alleles, and therefore, the presence of a *17 allele in combination with a nonfunctional allele would be considered an IM phenotype (see Table 5–2). The PM phenotype is more common in Asians (∼16%) than in Europeans and Africans (∼2–5%), which can be expected based on the inheritance patterns of variant alleles across populations, eg, the most common nonfunctional allele, ie, CYP2C19*2, is observed approximately twice as frequently in Asians (∼30%) compared with Africans and Europeans (∼15%), while the apparent gain-of-function *17 allele is observed rarely in Asians (< 3%) but more frequently in Europeans and Africans (16–21%) (see Table 5–1).
Example: Clopidogrel is a thienopyridine antiplatelet pro-drug indicated for the prevention of atherothrombotic events. Active metabolites selectively and irreversibly inhibit adenosine diphosphate-induced platelet aggregation (Chapter 34). Clopidogrel is metabolized in the body via one of two main mechanisms; approximately 85% of an administered dose is rapidly hydrolyzed by hepatic esterases to its inactive carboxylic acid derivative, while the remaining ∼15% is converted via two sequential CYP-mediated oxidation reactions (predominantly CYP2C19) to the active thiol metabolite responsible for antiplatelet activity.