Drug Metabolism, Poor, Cyp2c19-Related

A number sign (#) is used with this entry because poor metabolism of a wide variety of drugs, including mephenytoin, omeprazole, and proguanil, is caused by mutation in the CYP2C19 gene (124020).

Clinical Features

The antiepileptic drug mephenytoin is a racemate. Mephenytoin hydroxylation is a stereospecific reaction and is confined to the S-enantiomer, which is normally eliminated within hours. The R-enantiomer accumulates, requiring days or weeks for elimination. The inborn deficiency of mephenytoin hydroxylation prevents the rapid elimination of S-mephenytoin, which lingers in the body along with R-mephenytoin. Hydantoin levels in the blood are thus doubled, with toxic consequences. Kalow (1986) stated that there was no clinical evidence that the mephenytoin hydroxylation defect affects any other drug. Mephenytoin is 3-methyl 5,5-phenyl-ethyl-hydantoin. Phenytoin (see 132810), or diphenylhydantoin, is metabolized by a different system (Spielberg, 1988). Although both are anticonvulsants and chemically similar hydantoins, phenytoin and mephenytoin differ in their biologic action and their interaction with drug-metabolizing enzymes.

Andersson et al. (1992) found that in both Caucasians and Chinese the major metabolic pathway of omeprazole, a substituted benzimidazole that suppresses gastric acid secretion, cosegregates with the polymorphic metabolism of S-mephenytoin.

Inheritance

Kupfer and Preisig (1984) presented evidence that deficient capacity to hydroxylate mephenytoin is autosomal recessive and independent of the debrisoquine 4-hydroxylation defect (608902). By studies of 28 relatives of 5 poor metabolizers, Inaba et al. (1986) confirmed the autosomal recessive inheritance of deficient mephenytoin hydroxylation.

Population Genetics

Kalow (1986) stated that the frequency of poor mephenytoin metabolizers was about 5% among 459 Canadians of European extraction. The poor metabolizer phenotype occurred in 7 of 31 Japanese-Canadians and 2 of 39 Chinese-Canadians.

Wood (2001) discussed pointers to genetic differences underlying racial differences in the response to drugs. The proton-pump inhibitor omeprazole is metabolized by CYP2C19, which is one of the drug-metabolizing enzymes that exhibits polymorphism with phenotypes of varying distributions among different racial groups (Xie et al., 2001). For CYP2C19, in contrast to CYP2D6 (124030), the phenotype of poor metabolism is relatively rare in whites (occurring in less than 2%) but is frequent in Asians (occurring in 18 to 20%). Omeprazole is frequently used as part of a combination regimen to eliminate Helicobacter pylori in patients with peptic ulcer disease, and the rate of response is dependent on the CYP2C19 genotype, ranging from 28% in patients who are homozygous for the extensive metabolism allele to 100% in those with poor metabolism (Furuta et al., 1998).

Molecular Genetics

The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2 to 5% of Caucasians and 18 to 23% of Japanese subjects, the specific cytochrome P-450 isozyme, mephenytoin 4-prime-hydroxylase, is functionally deficient or missing. Meier and Meyer (1987) accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid-induced hepatitis specifically recognize the cytochrome P-450 involved in the mephenytoin hydroxylation polymorphism. They immunopurified this cytochrome P-450 from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of S-mephenytoin. They could not demonstrate any structural difference between the 2 isozymes.

CYP2C19 is the cytochrome P450 enzyme that is the site of the defect in metabolism of mephenytoin and a number of other drugs. The molecular defect in CYP2C19 responsible for the poor metabolizer phenotype was identified by de Morais et al. (1994) and is referred to as the CYP2C19*2 allele (124020.0001). Several other defective CYP2C19 alleles, including CYP2C19*3 (124020.0003), CYP2C19*4 (124020.0004), and CYP2C19*5 (124020.0002), have also been reported in association with the poor metabolizer phenotype.

Proguanil, which is metabolized in the liver to its active form, cycloguanil, is recommended for malaria chemoprophylaxis in the face of chloroquine resistance in Plasmodium falciparum. Kaneko et al. (1997) noted that proguanil and mephenytoin metabolisms cosegregate, suggesting that poor mephenytoin metabolizers would also show poor therapeutic efficacy of proguanil. Using PCR, Kaneko et al. (1997) determined the distribution of the CYP2C19*2 and CYP2C19*3 mutations in 493 individuals from 2 of the 80 islands of Vanuatu in Melanesia. The CYP2C19*2 allele represented 698 of 986 alleles (70.6%), and the CYP2C19*3 allele represented 131 of 986 alleles (13.3%). Only 145 individuals had at least 1 wildtype allele. By analyzing serum concentrations of proguanil and cycloguanil, Kaneko et al. (1997) found that the CYP2C19 genotype predicted the proguanil metabolism phenotype of all 20 patients examined. The data suggested that 348 of the 493 individuals (70.6%) studied had the poor metabolizer phenotype, a finding with major implications for the efficacy of proguanil in this population.

Among 1,419 patients with acute coronary syndrome on dual antiplatelet treatment, including clopidogrel and aspirin, Giusti et al. (2007) found an association between carriers of the CYP2C19*2 polymorphism and increased residual platelet reactivity, as evaluated by platelet aggregation studies. The active metabolite of clopidogrel arises from complex biochemical reactions involving several P450 isoforms, including CYP2C19.

Pare et al. (2010) genotyped patients from 2 large randomized trials that showed that clopidogrel, as compared with placebo, reduced the rate of cardiovascular events among patients with acute coronary syndromes and among patients with atrial fibrillation. Patients were genotyped for 3 SNPs (*2, *3, *17) that define the major CYP2C19 (124020) alleles. Among 5,059 genotyped patients with acute coronary syndromes, clopidogrel as compared with placebo significantly reduced the rate of the primary efficacy outcome, irrespective of the genetically determined metabolizer phenotype. The effects were similar in patients who were heterozygous or homozygous for loss-of-function alleles and in those who were not carriers of the alleles. In contrast, gain-of-function carriers derived more benefit from clopidogrel as compared with placebo than did noncarriers. The effect of clopidogrel on bleeding did not vary according to genotypic subgroups. Among 1,156 genotyped patients with atrial fibrillation, there was no evidence of an interaction with respect to either efficacy or bleeding between the study treatment and the metabolizer phenotype, loss-of-function carrier status, or gain-of-function carrier status.

Geisler et al. (2011) suggested that a conclusive judgment regarding the relationship between CYP2C19 variants and the efficacy and safety of clopidogrel treatment may be premature, and suggested a systematic investigation of cis- and trans-genetic determinants with the use of new interactome models. Similarly, Siasos et al. (2011) suggested that further studies were needed to evaluate the contribution of the genomic profile in the individual antiplatelet response, including not only the 3 studied polymorphisms in CYP2C19, but also all the polymorphic genes involved in the pharmacokinetic and pharmacodynamic response to clopidogrel. Pare et al. (2011) agreed with Geisler et al. (2011) and Siasos et al. (2011).