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.

[Maintenance dose requirement for phenytoin is lowered in genetically impaired drug metabolism independent of concommitant use of other antiepileptics]. / Benodigde dagdosis fenytoïne verlaagd bij genetisch bepaald traag geneesmiddelmetabolisme en onbeïnvloed bij gelijktijdig gebruik van andere anti-epileptica.

OBJECTIVE: To investigate the effect of genetically determined impaired drug metabolism and of the use of comedication on phenytoin maintenance dose requirement. DESIGN: Descriptive. METHOD: In 60 patients on long-term phenytoin therapy the concentration of phenytoin in serum was measured and CYP2C9 genotyping was performed (mutant alleles of CYP2C9 are associated with impaired phenytoin metabolism). In addition, the use of other antiepileptics concurrently with phenytoin was reviewed: phenobarbital, carbamazepine and valproic acid. CYP2C9 genotype and comedication were connected to phenytoin daily dose requirement. The 60 patients were 38 men and 22 women, between 16 and 74 years of age, and all mentally disabled. RESULTS: Genotyping revealed that of the 60 patients 38% (n = 23) carried at least one mutant CYP2C9 allele. Their mean dose of phenytoin was 199 mg dd, while the mean required maintenance dose in non-carriers (n = 37) was 287 mg dd (p < 0.01). When the use of comedication was taken into account, it appeared that the mean phenytoin daily doses in the different comedication groups did not differ significantly. CONCLUSION: Patients with a genetically determined impaired phenytoin metabolism required on average a 30% lower dose than those with a normal metabolism, while the concomitant use of other antiepileptics appeared to have no effect on phenytoin dose requirement.