Cytochrome P450 Enzymes CYP2C19 Research Articles

The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement.

The cytochrome P450 enzyme CYP2C9 catalyses the metabolism of numerous therapeutic agents, including the anti-epileptic drug phenytoin. CYP2C9 is genetically polymorphic: two allelic variants are known, CYP2C9*2 and CYP2C9*3, differing from the wild-type CYP2C9*1 by a single point mutation. Both mutant alleles are associated with markedly impaired metabolic capacity for many CYP2C9 substrates compared to the wild-type, resulting in raised serum drug levels upon a given dose. Because this may be relevant in treatment with phenytoin, we studied the effect of CYP2C9 genotype on phenytoin dose requirement in a group of 60 epileptic patients on long-term phenytoin therapy. CYP2C9 genotyping was performed by polymerase chain reaction analysis, phenytoin serum concentrations were measured by high-performance liquid chromatography analysis and related to the maintenance doses. For patients carrying at least one mutant CYP2C9 allele (n = 17), the mean phenytoin dose required to achieve a therapeutic serum concentration was about 37% lower than the mean dose required by wild-type individuals (199 mg/day versus 314 mg/day; P < 0.01). A low maintenance dose (< 200 mg/day) sufficed for 47% of carriers, while 58% of normals required a high dose (> 300 mg/day) for an effective serum level. The results show that there is a strong association between CYP2C9 allelic variants and phenytoin dose requirement. Since phenytoin has a narrow therapeutic index and genotyping may be carried out rapidly and at low cost, dosage adjustment based on CYP2C9 genotype, especially at the induction of therapy, would be of value in order to lower the risk of concentration dependent drug intoxications in carriers.

Therapeutic drug monitoring as a tool in treating HIV infection.

Despite its success antiretroviral therapy (ART) is still associated with a significant risk of toxicity and subsequent virological failure. Pending the introduction of drugs with greater potency and durability one of the most pressing priorities in HIV treatment is to identify ways in which to maximize the efficacy of existing therapeutic options while minimizing its toxicity. Resistance testing has been shown to be one such strategy. Therapeutic drug monitoring (TDM) for HIV drugs has been widely proposed as another tool by which treatment may be optimized. There are some parallels with resistance testing not least the potential difficulties or pitfalls in interpreting test results and the understandable pressure for provision of this service in the face of increasingly limited treatment options notwithstanding the current lack of data from controlled clinical studies. In this reviews we shall discuss the value of TDM in the context of a ‘monitoring service (in other words drug concentrations are provided in conjunction with interpretation and advice) rather than a facility for ‘measuring drug concentrations. This distinction is important since the interpretation of drug concentrations is fraught with complexity. (excerpt)

Frequency of cytochrome P450 CYP2C9 variants in a Turkish population and functional relevance for phenytoin.

The genetically polymorphic cytochrome P450 enzyme CYP2C9 metabolizes many important drugs. We studied the frequency of the amino acid variants cysteine144 (CYP2C9*2 ) and leucine359 (CYP2C9*3 ) in a Turkish population and the correlation between genotype and phenotype using phenytoin as probe drug. CYP2C9 alleles *2 and *3 were measured in 499 unrelated Turkish subjects by PCR and restriction fragment length pattern analysis. Phenotyping was performed in a subgroup of 101 volunteers with a single oral dose of 300 mg phenytoin and concentration analysis in serum drawn 12 h after dosage. CYP2C9 allele frequencies in 499 unrelated Turkish subjects were 0.794 for CYP2C9*1, 0.106 for CYP2C9*2 and 0. 100 for CYP2C9*3. Mean phenytoin serum concentrations at 12 h after dosage were 4.16 mg l-1 (95% CI 3.86-4.46) in carriers of the genotype CYP2C9*1/1, 5.52 mg l-1 (4.66-6.39) in CYP2C9*1/2, and 5.65 mg l-1 (4.86-6.43) in CYP2C9*1/3. These differences were significant and accounted for 31% of total variability in phenytoin trough levels. Mean 12 h concentration ratios of 5-(para-hydroxyphenyl)-5-phenylhydantoin/phenytoin (p-HPPH/P) were 0. 43 (0.39-0.47) for CYP2C9*1/1 compared with 0.26 (0.21-0.31) for CYP2C9*1/2, 0.14 (0.13-0.14) for CYP2C9*2/2, 0.21 (0.18-0.24) for CYP2C9*1/3, and 0.02 for CYP2C9*3/3; all mutant genotypes were significantly different compared with CYP2C9*1/1. Frequency of the two CYP2C9 variants in Turkish subjects was in a similar range as in other Caucasian populations. A significant proportion of the interindividual variability in phenytoin trough levels is explained by the genotypes. The 12 h serum concentrations after a single phenytoin dose may be used for routine phenotyping of CYP2C9 mediated metabolic clearance and the p-HPPH/P ratios may be even more sensitive indicators of CYP2C9 activity.