Different pharmacokinetic parameters of phenytoin in Iranian Outpatients: Need to optimize the current dosage administration

Dose-dependent pharmacokinetic of phenytoin necessitates the estimation of the maximum rate of metabolism (Vm) and the Michaelis-Menten constant (Km) in a concerned population. The aim of this study was to determine the pharmacokinetic parameters of phenytoin in a sample of Iranian patients to optimize the antiepileptic pharmacotherapy. Fourty patients who received a constant dose of phenytoin for at least three weeks were included in the study. Steady-state trough serum concentration has been used to determine the Vm and Km by Vozeh-Sheiner (orbit-graph) method. Mann-Whitney U-test and chi-square test have been used to compare the quantitative and qualitative variables respectively. Only half of the patients were in the therapeutic range. Mean Vm and mean Km were 6.12±1.01 mg/kg/day and 5.90±1.26 mg/l respectivly with significant differences [95% confidence interval of difference with the reported to mean values of 7 mg/Kg/day for Vm and 4 mg/l for Km interval -0.88 (-1.2 to 0.55) and +1.9 (1.49 to 2.31) respectively]. A trend towards higher clearance (CL) and intrinsic clearance (CLint) were observed in patients on polytherapy with phenobarbital compared to those on phenytoin monotherapy. Advanced age was inversely associated with the values of Vm and CLint in the group on monotherapy. Considering the observed lower Vm and higher Km, our population may have a lower metabolic capacity for metabolism of phenytoin, and using the estimates of Vm and Km obtained this study could help the clinicians to individualize antiepileptic therapy. In addition, the results of this study may propose that the expression of CYP2C9 and CYP2C19, as two main pathways of phenytoin metabolism, may be lower in iranians than the other populations, and phenotyping/genotyping studies of these pathways are recommended.