Influence of the CYP2C9 AND CYP2C19 polymorphisms on phenytoin hydroxylation in healthy individuals from south India.

BACKGROUND AND OBJECTIVES: Phenytoin, a widely used anti-epileptic drug, is metabolized mainly by CYP2C9 (90%) and partly by CYP2C19 (10%) to its major metabolite 5-(para-hydroxyphenyl)-5- phenylhydantoin (p-HPPH). The CYP2C9 and CYP2C19 genes encoding these enzymes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 as well as CYP2C19*2 and *3 variant genotypes on phenytoin hydroxylation in healthy subjects from south India. METHODS: A total of 27 healthy, unrelated, subjects were administered a single oral dose of 300 mg phenytoin. Four hours later, 5 ml of blood was collected and genotyped for CYP2C9*1, *2, *3, CYP2C19*1, *2 and *3 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Phenytoin and the major metabolite p-HPPH were estimated by reverse phase HPLC. The metabolic ratio was calculated as concentration of phenytoin/p-HPPH. RESULTS: A significant correlation was observed between the CYP2C9 genotype and metabolic ratio of phenytoin/p-HPPH (r = 0.472, 95% CI 0.100 to 0.728; P = 0.01). While no association was found with CYP2C19 alone, a significant correlation was observed between the combined CYP2C9 and CYP2C19 genotypes and phenytoin metabolic ratio (r = 0.507, 95% CI 0.146 to 0.749; P< 0.01). INTERPRETATION AND CONCLUSION: CYP2C9*2 and *3 mutant alleles caused decreased hydroxylation of phenytoin in vivo, whereas the mutant alleles of CYP2C19 played only a minor role in the metabolism of phenytoin in subjects of our study. The results of present preliminary study needs to be confirmed with a larger sample.

Serum protein binding of antiepileptic drugs in Sri Lankans.

The percentage protein binding of antiepileptic drugs was investigated in epileptic patients (n = 90) undergoing treatment with phenobarbitone, phenytoin and carbamazepine either as a single drug therapy or in different combinations. When administered individually, the percentage (mean +/- SEM) protein binding of phenobarbitone, phenytoin and carbamazepine were 50.84 +/- 7.03, 87.23 +/- 2.98 and 76.80 +/- 6.30 respectively. Combination of phenobarbitone and phenytoin resulted in percentage (mean +/- SEM) protein binding of 51.94 +/- 6.09 for phenobarbitone and 83.54 +/- 7.01 for phenytoin, while the combination of phenobarbitone and carbamazepine resulted in percentage (mean +/- SEM) protein binding of 49.60 +/- 2.59 for phenobarbitone and 79.10 +/- 3.31 for carbamazepine. When phenytoin was given with carbamazepine percentage (mean +/- SEM) protein binding was 87.22 +/- 4.48 for phenytoin and 72.50 +/- 5.92 for carbamazepine.

Estudio de biodisponibidad de tres formulaciones de difenilhidantoinato sódico / Bioavailability study of 3 formulations of sodium diphenylhydantoinate

Se estudió la biodisponibilidad de tres formulaciones de difenilhidantoinato de sodio en 26 varones voluntarios sanos que recibieron una dosis única de 100 mg por la vía bucal a las 7 a.m. Las formulaciones A y B provenían de proveedores del Instituto Mexicano del Seguro Social, y se obtuvieron de sus Almacenes Centrales. La formulación C o producto innovador se adquirió en una farmacia de venta al público. Como testigo se preparó la formulación D de un estándar conocido, a la misma concentración que las precedentes (100 mg/100 ml de agua). Las formulaciones A y B mostraron un buen porcentaje de disolución (94.89 + ou - 4.07 y 109.20 + ou - 2.98 por ciento respectivamente) y una buena absorción según los resultados de la concentración plasmática máxima (Cmax), el tiempo necesario para alcanzarla (tmax) y el área, bajo la curva de las concentraciones estudiadas, del tiempo 0 a 12 horas (ABC0-12). La formulación C presentó un porcentaje de disolución bajo (24.12 + ou - 3.15 por ciento) y valores inferiores de los otros aspectos estudiados