ABSTRACT
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.
Subject(s)
Adult , Anticonvulsants/metabolism , Aryl Hydrocarbon Hydroxylases/genetics , Female , Genotype , Humans , Hydroxylation , India , Male , Mixed Function Oxygenases/genetics , Phenytoin/metabolism , Polymorphism, Single NucleotideABSTRACT
Therapeutic drug monitoring (TDM) of carbamazepine (CBZ) in saliva is an attractive alternative, because its collection is painless, non-invasive and simpler than drawing blood. Salivary drug levels, also closely reflect the free drug concentration. The aim of the study was to evaluate the suitability of saliva in routine TDM of CBZ in adult epileptic patients. Blood and saliva samples were taken simultaneously at 0 hours and 24 hours of CBZ dosing from 31 epileptic patients, receiving CBZ monotherapy for three or more months. Levels of CBZ in both these fluids were measured by high performance liquid chromatography. Strong and highly significant correlation was found between serum and salivary CBZ concentration (r = 0.659, p<0.001). Estimation of CBZ level in saliva is thus a practicable, valid and convenient method of TDM in epileptic patients.
Subject(s)
Adolescent , Adult , Anticonvulsants/metabolism , Blood/metabolism , Carbamazepine/metabolism , Drug Monitoring , Epilepsy/drug therapy , Humans , Middle Aged , Osmolar Concentration , Saliva/metabolismABSTRACT
Se estudiaron prospectivamente 20 pacientes embarazadas, epilepticas, controladas en la consulta de psiquiatria de la Maternidad Concepcion Palacios, de Caracas, entre julio de 1985 y octubre de 1986. Se midieron las concentraciones plasmaticas de los anticonvulsivos que recibieron, en dos momentos del embarazo, a intervalos de entre 8 y 12 semanas. Se determino tambien la relacion entre la dosis diaria en mg. por kilo de peso y la concentración plasmatica (depuracion aparente). Se analizaron los datos en 10 pacientes pues las restantes no llenaron los requisitos del proyecto. A todas se les practico E.E.G. cinco pacientes recibieron difenilhidantoina, una fenobarbital, tres difenilhidantoina asociada a fenobarbital, una fenobarbital asociada a valproato de sodio. Todas recibieron suplemento con hierro y acido folico