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.

Clozapine is an atypical antipsychotic drug that is metabolized to a major extent by the cytochrome P450 enzyme CYP1A2. Smoking is a potent inducer of CYP1A2 enzyme activity, resulting in significant lower clozapine serum concentrations in smokers compared with non-smokers, upon a given dose. Recently, a single nucleotide polymorphism identified at position 734 of the CYP1A2 gene, was reported to affect the inducibility of the enzyme. Because this polymorphism in relation to smoking behaviour may be relevant in treatment with clozapine, we studied the effect of CYP1A2 genotype on clozapine clearance and dose requirement in a group of 80 smoking and non-smoking schizophrenic patients on long-term clozapine therapy. Clozapine serum concentration and CYP1A2 genotype had been determined routinely by high-performance liquid chromatography and polymerase chain reaction analyses, respectively. In smokers, the clozapine serum concentration corrected for dose (C/D ratio) was on average 2.5 times lower compared with non-smokers, indicating an enhanced clearance. The mean required maintenance doses of clozapine for smokers and non-smokers were 382 mg/day and 197 mg/day, respectively (P < 0.01). Neither among smokers, nor among non-smokers mean C/D ratios and daily doses did vary significantly between patients with the different CYP1A2 genotypes. The results show that clozapine clearance and daily dose requirement are strongly associated with smoking behaviour, while the CYP1A2 genetic polymorphism seems to have no significant clinical effect. Dosage adjustment based on smoking behaviour would be of value in order to lower the incidence of non-therapeutic serum drug levels and, consequently, intoxication or inadequate antipsychotic response.

In the psychiatric setting, therapeutic drug monitoring and genotyping for cytochrome P450 (CYP) polymorphisms help to ensure and maintain therapeutic drug levels. In this study, the authors extended the therapeutic drug monitoring and genotyping protocol routinely used in their psychiatric clinic to primary care patients treated with antidepressants. They examined the variation in serum concentrations and assessed the role of CYP polymorphisms, wrong dosing, and noncompliance in deviating serum concentrations. Of 227 serum concentrations obtained, 127 (56%) were more than 20% outside therapeutic ranges. Of these 127 cases, 64 (50%) were congruous with aberrant CYP2D6 or CYP2C19 genotypes, incorrect dosing, or a pharmacy record suggesting noncompliance. Prevalence of aberrant CYP2D6 and CYP2C19 genotypes did not differ significantly between the investigated primary care patients and 751 secondary care users of antidepressants. The therapeutic drug monitoring and the genotyping findings resulted in recommendations to physicians to alter the medication strategy of 146 (64%) patients. These results strongly suggest that the rationale for therapeutic drug monitoring and CYP genotyping when prescribing antidepressants in secondary care also applies to the primary care setting.