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

Abstract

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.

Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research

“…44,63,76 Several variants related to decreased activity of CYP2C9 and CYP2C19 have been detected, 77,78 and one CYP2C19 variant (*17) with increased transcription in vitro has been described. 77 Aside from lower dose requirements, 28,79 no connection between these variants and level of response to psychotropic drugs has been reported. CYP2C19 may be clinically relevant for the metabolism of antidepressants but has very limited significance for antipsychotic metabolism.…”

Influence of CYP2C9 genotypes on the formation of a hepatotoxic metabolite of valproic acid in human liver microsomes

“…26,27 In contrast, the heterozygote CYP2C9*2 and CYP2C9*3 genotypes are more common, with a prevalence of up to 19% in Caucasians. [26][27][28] Relatively little is known about the functional consequences of these heterozygote Figure 4 were stratified according to the number of mutated CYP2C9 alleles; none (CYP2C9*1/*1; N¼12), one (CYP2C9*1/*2 and CYP2C9*1/*3; N¼18), or two (CYP2C9*2/*2, CYP2C9*2/*3, and CYP2C9*3/*3; N¼9). Results are expressed as mean7SEM.…”

Prevalence of CYP2C9 polymorphisms in the south of Europe

“…Population diversity CYP2C9*2 and *3 allele frequencies were compared among the sampled populations and also among data previously published for 12 European populations scattered all over the continent from the United Kingdom, 17 Holland, 18 France, 16 Germany, 19 Hungary, 20 Italy, 21 Sweden, 22 Turkey, 12 Belgium, 13 Iran, 14 Spain 11 and the Europeans from the United States of America 23 (Table 4). No significant differences were observed among our five samples in any of the CYP2C9 variants.…”

“…[11][12][13][14][15][16][17][18][19][20][21][22][23] Here we present a descriptive study of the prevalence of the most relevant CYP2C9 polymorphisms, CYP2C9*1 (wild type), CYP2C9*2 and CYP2C9*3, in population samples from both Spain (Basque Country, Catalonia, Central Spain and Galicia) and northern Italy (Verona) summing up a total of 1240 individuals. We also compared the allele frequencies on our population samples with those previously published for other European populations.…”