Effect of CYP3A5 polymorphism on carbamazepine pharmacokinetics in Thai patients as monotherapy or coadministration with phenytoin, phenobarbital or valproic acid

Abstract

There were three main purposes in this present study; first, to compare clearance, level-to-dose ratio of carbamazepine (CBZ) between patients with CYP3A5*1 and CYP3A5*3 alleles either when CBZ was used as monotherapy or coadministration with phenytoin (PHT), phenobarbita (PB) or valproic acid (VPA), second, to provide regression equation to predict CBZ clearance from demographic data and polymorphism of CYP3A5, third, to determine relationship between CBZ clearance and the maximum rate of metabolism of PHT (Vmax), PB clearance and VPA clearance. A retro-prospective data were collected at the epilepsy outpatient clinic of Prasat Neurological Institute, Bangkok. Genotyping of CYP3A5 was performed in 70 patients. The allele frequency of CYP3A5*1 was 31% and CYP3A5*3 was 69%. The CBZ clearance and level-to-dose ratio was not significantly diffferent between patients with CYP3A5*1 and CYP3A5*3 alleles. However, in patients who used CBZ in combination with enzyme inducing antiepileptic drug (PHT or PB), individuals carrying CYP3A5*1 allele yielded the trend toward more susceptible to changes in CBZ clearance and showed lower CBZ-level-to dose ratio as compared to invividuals carrying CYP3A5*3 allele. Multiple regression analysis for prediction of CBZ clearance from demographic data and CYP3A5 genotypes (N=70), which excluded CYP3A5 genotypes while selected four other factors generated the model as being related to CBZ clearance (L/kg/day); CBZ dose (mg/kg), PHT dose (mg/kg), PB dose (mg/kg) and body weight (kg), this model could explain 54.7% of the variance in CBZ clearance (p<0.0001). When two antiepileptic drugs were used concurrently, PHT Vmax showed high correlation with CBZ clearance (N=14, R²=78%, p<0.001)), VPA clearance showed moderate correlation with CBZ clearance (N=16, R²=41.2%, p=0.007)) while the correlation between PB clearance and CBZ clearance was not reach the statistically significant level (N=15R² = 11%, p=0.227).