Cytochromes P450 enzymes are essential for the metabolism of many medications, the major phase I enzymes including: CYP2C9, CYP2C19, and CYP2D6 are highly polymorphic and account together for about 40% of hepatic human phase I metabolism. These enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. CYP2C19 is a liver enzyme and is responsible for metabolizing a wide variety of drugs including the anticoagulant clopidogrel (Plavix), antiulcer drugs such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.
People who have reduced functioning of their CYP2C19 enzyme due to inactivating polymorphisms cannot effectively convert Plavix to its active form. As a result, Plavix may be less effective in altering platelet activity in those people. Those poor metabolizer patients may not receive the full benefit of Plavix treatment and may remain at risk for heart attack, stroke, and cardiovascular death. The polymorphism of the CYP2C19 enzyme results in poor, intermediate, moderate or rapid or extensive metabolizers of CYP2C19 drugs.
The CYP2C19 gene is mapped to chromosome 10q23.33 and encodes an enzyme of 490 amino acids. The CYP2C19*1 allele represents the wild-type allele. Considerable ethnic differences have been reported in the incidence of poor metabolizer (PM) genotypes of cytochrome P450 (CYP) 2C19. In poor metabolizers, two alleles are most frequently observed: a splice defect in exon 5 (CYP2C19*2; single base change G>A), and a premature stop codon at position 636 of exon 4 (CYP2C19*3; single base change G>A). The CYP2C19*2 polymorphism occurs almost exclusively in Caucasians; while the CYP2C19*3 polymorphism occurs in Asians. In general, rapid or extensive metabolizer with increased enzyme activity is used for *1/*1, intermediate metabolizer with moderate enzyme activity for *1/*2 and *1/*3, and poor metabolizer with reduced enzyme activity for *2/*2, *2/*3 and *3/*3.
Shilbayeh et al. (2006) evaluated the pharmacokinetic parameters of omeprazole after a single dose in 74 healthy Jordanian subjects. The study took place at Al Essra Hospital in Amman. After an overnight fast, omeprazole was administered as a single Losec 20mg capsule. A total of 20 blood samples were collected over a 10-hour period after administration. The mean pharmacokinetic parameters and their corresponding coefficient of variation (CV%) for peak plasma concentration (Cmax), AUC from time zero to infinity (AUCinfinity), time to reach Cmax (tmax), apparent oral clearance (CL/F) and elimination half-life [t(1/2)] were 314.96 ng/mL (56%), 923.2 ng h/mL (108.6%), 2.1h (44%), 0.66 L/h/kg (92%), and 1.5 h (56.6%), respectively. The study revealed that the majority of the Jordanians seemed to be more properly classified within the EM phenotype and that the observed metabolic rates of heterozygous and homozygous Jordanians were more comparable to those of Caucasian EMs than Oriental EMs. Shilbayeh et al. (2006) speculated that higher dosage requirements can be expected among most of Jordanians. Yet, they also indicated that the incidence of PMs is significant and they seemed to exhibit a similar pharmacokinetic pattern to Chinese PMs in terms of long-term exposure (clearance and AUC) as well as short-term exposure (Cmax) parameters, after adjustment for dose and bodyweight.
Evans et al. (1995) studied the frequency of the CYP2C19 alleles among Saudi Arabian and Filipino volunteers. The study included 102 healthy Saudis (92 males, 10 females) with an average age of 25 years. Two Saudi volunteers were found to have poor metabolism (PM) phenotype, while the other 100 were extensive metabolizers (EM) of the S-mephenytoin.
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