engleski

Genetic polymorphismes of Cytochromes P450: CYP2C9, CYP2C19 and MDR1 genes and their effect on phenytoin disposition

Background and Purpose: Anticonvulsant drug phenytoin exhibits non linear pharmacokinetics with large interindividual differences. Phenytoin is a substrate of CYP2C9 and CYP2C19, and the P- glycoprotein encoded by the MDR1 gene. We assessed the polymorphisms of CYP2C9, CYP2C19 and MDR1, and their effects on the phenytoin disposition by evaluating the correlation of phenytoin (PHT) and phenytoin metabolic ratio (PMR) with polymo)phisms of CYP2C9, CYP2C19 and C3435T in the MDR1 gene. Materials and Methods: Sixty-four healthy volunteers were included in the study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) were performed for the most frequent alleles: CYP2C9*1, *2, *3, CYP2C19*1*2, *3, and C3435T - MDR1. The 12h-serum concentrations after 300 mg oral dose of phenytoin were used for phenotype analysis. Phenytoin (PHT) and main metabolite (p-HPPH) were analyzed by HPLC. Results: The highest phenytoin serum concentrations (6.52 +/- 0.56 mg/L) were in subjects with CYP2C9*2/*2 plus CYP2C19*2/wt genotype and were significantly different from the lowest concentrations (3.95 +/- 0.83 mg/L) in subjects with wt/wt genotypes (p < 0.01). The highest PMR values (0.48 +/- 0.05) were noted in homozygous subjects for CYP2C9*wt plus CYP2C19*wt and the lowest PMR value (0.08) in homozygous subjects for defective alleles CYP2C9*2 plus CYP2C19*2 whereas heterozygous subjects had intermediate values (0.26 +/- 0.06) with the major role of polymorphic CYP2C9. Phenytoin serum levels and metabolic ratios were significantly different in subjects with MDR1 CC genotype from those in subjects with MDR1 TT genotype: p < 0.05. Conclusion: analysis of CYP2C9, CYP2C19 and MDR1 genotypes could have predictive value for phenytoin disposition in clinical practice.

CYP2C9 ; CYP2C19 ; MDR1 ; phenytoin ; metabolic ratio ; genotype

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