Dosage Recommendation of Phenytoin for Patients with Epilepsy with Different CYP2C9/CYP2C19 Polymorphisms

Abstract

To search for the optimal dosage of phenytoin in patients with epilepsy based on the metabolic activities of CYP2C9 and CYP2C19 polymorphisms, a total of 169 patients receiving phenytoin treatment for more than 1 month were recruited. Phenytoin concentration, serum albumin, liver function tests, and renal function tests were measured. CYP2C9 and CYP2C19 polymorphisms were genotyped by PCR-RFLP analysis, and NONMEM models were built to evaluate factors that would affect phenytoin metabolism. Patients were divided into 5 groups according to genotyping results (G1 to G5). Compared with extensive metabolizers in both CYP2C9 and CYP2C19 (G1), the Vmax (mg/kg/d) was 8.29% and 36.96% lower in CYP2C19 poor metabolizers (G3) and CYP2C9 poor metabolizers (G4), respectively. For the patient who was identified as a poor metabolizer in both CYP2C19 and CYP2C9 (G5), the Vmax was 45.75% lower than that of G1. In respect to Km (mg/L), it was 15.09% higher in G3 and 27.36% higher in G4 compared with that in G1. The Km of G5 was 91.71% higher than that of G1. The results revealed that the CYP2C9 and CYP2C19 polymorphisms have dramatic effects on the population pharmacokinetic parameters of phenytoin, especially for CYP2C9. Based on the Vm and Km values obtained in this study, the recommended dose ranges for G1, G2, G3, G4, and G5 patients would be 5.5-7, 5-7, 5-6, 3-4, and 2-3 mg/kg/d, respectively.

CYP2C9 polymorphism in patients with epilepsy: genotypic frequency analyzes andphenytoin adverse reactions correlation

“…However, it seems to be clear that several factors may contribute to the lack of correlation between CYP2C9 genetic polymorphism and PAR. Not only CYP2C9 but also CYP2C19 has been reported to catalyze phenytoin 8,14 . Some studies also indicate the role of P-glycoprotein in the disposition of phenytoin.…”

“…Genetic variation in the CYP2C9 gene can affect metabolism, leading to altered phenotypes. Individuals with poor metaboliser alleles of CYP2C9 gene were shown to have a reduced metabolism of phenobarbital, phenytoin and valproate compared with those with wild-type (normal) alleles [2][3][4][5][6][7][8][9] . Several studies indicate that the most common allelic variants are Arg 144 Cys (CYP2C9*2) and Ile 358 Leu (CYP2C9*3) which encode enzymes with decreased substrate turnover 10,11 .…”

“…Its main rout of elimination is through hepatic oxidation under CYP2C9 (90%) and CYP2C19 (10%) metabolism 8,14,15 . Phenytoin metabolism rate can be reduced by 25 to 50 % depending on the individual genetic polymorphism and drug interactions through same pathway 2,8,14,16 . Its use can be associated to several dose related or idiosyncratic adverse events.…”

Defining the clinical role of pharmacogenetics in antiepileptic drug therapy

“…First, the initial association between polymorphism in genes for the PHT metabolizing enzyme CYP2C9 and pharmacokinetic parameters of PHT treatment 5,6 has been confirmed. 7 More recent studies provide additional confirmation of influence of CYP2C9 genotype on PHT treatment by showing that patients harboring the *3 allele exhibit a modest (10-15%) but significant reduction in maximum tolerated dose of PHT. 8 It is estimated that only a small portion (less than 10%) of the variance in the maximum tolerated dose of PHT was explained by polymorphism at the CYP2C9 locus.…”

“…In another study, estimated daily doses required to keep PHT in the usual reference boundaries of 10-20 mg/l ranged from 2-3 to 5.5-7 mg/kg/day based on genotyping of polymorphisms in CYP2C9 and CYP2C19. 7 The other genetic factor putatively associated with AED treatment is SCN1A. 8 It represents the first strong association between a clinically relevant AED end point and a gene that encodes a therapeutic target for the AED and if confirmed could have a significant impact on treatment paradigms.…”