Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms

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 V_max (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 V_max was 45.75% lower than that of G1. In respect to K_m (mg/L), it was 15.09% higher in G3 and 27.36% higher in G4 compared with that in G1. The K_m 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 V_m and K_m 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.