The effect of polymorphic metabolism enzymes on serum phenytoin level

Abstract

Phenytoin has a widespread use in epilepsy treatment and is mainly metabolized by hepatic cytochrome P450 enzymes (CYP). We have investigated CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 allelic variants in a Turkish population of patients on phenytoin therapy. Patients on phenytoin therapy (n = 102) for the prevention of epileptic seizures were included. Polymorphic alleles were analyzed by restriction fragment length polymorphism method. Serum concentrations of phenytoin were measured by fluorescence polarization immune assay method. The most frequent genotype was detected for CYP2C9 wild-type alleles (78.43 %), whereas CYP2C19*2/*2 (5.88 %) was the least frequent genotype group. According to the classification made with both enzyme polymorphisms, CYP2C9*1/*1-CYP2C19*1/*1 (G1: 41.17 %) genotype group was the most frequent whereas CYP2C9*1/*2-CYP2C19*1/*3 (G7: 0.98 %) was the least frequent one. The highest mean phenytoin level (27.95 ± 1.85 µg/ml) was detected in the G8 genotype group (CYP2C9*1/*3-CYP2C19*2/*3) and the G1 genotype group showed the lowest mean phenytoin level (7.43 ± 0.73 µg/ml). The mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients. These results show the importance of the genetic polymorphism analysis of the main metabolizing enzyme groups of phenytoin for the dose adjustment.

Frequencies of CYP2C9 polymorphisms in North Indian population and their association with drug levels in children on phenytoin monotherapy

“…Similarly the mean serum concentration of phenytoin of the polymorphic patients with epilepsy was higher than that for the wild-type alleles both in the monotherapy and polytherapy patients in a study done by Ozkaynakci A et al [ 24 ].…”

Lower CYP2C9 activity in Turkish patients with Behçet’s disease compared to healthy subjects: a down-regulation due to inflammation?

“…The cytochrome P450 isoenzyme CYP2C9 plays an important role in the metabolism of many therapeutically important drugs such as phenytoin [14], S-warfarin [15], tolbutamide [16], losartan [17], and non-steroidal anti-inflammatory agents (NSAIDs) [13] in vitro and/or in vivo. Inter-individual differences in CYP2C9 metabolic activity have been linked to dosing difficulty that might lead to ineffective treatments or worse, toxicity [18].…”

Impact of Genetic Polymorphisms on Phenytoin Pharmacokinetics and Clinical Outcomes in the Middle East and North Africa Region

“…Both variants exhibit reduced functional activity, with losses of 29 and 94% enzymatic activity reported for CYP2C9*2 and *3 , respectively, when compared with the wild-type genotype [ 125 , 126 ]. Three of the included studies investigated CYP2C9 genotypes [ 42 – 44 ].…”

“…Ozkaynakci et al [ 44 ] reported data for 11 different combinations of CYP2C9 and CYP2C19 genotypes; therefore, the independent impact of the CYP2C9 genotype on serum phenytoin concentrations was difficult to discern. When compared with the CYP2C9 and CYP2C19 wild-type genotype group, CYP2C9*1/*3 , CYP2C19*2/*3 was the only genotype group with a serum phenytoin trough that was significantly different, with a mean concentration that was 20.47 mg/L higher than the wild-type genotype group ( p < 0.001).…”