Association Study Of CYP3A5 Genetic Polymorphism With The Serum Concentrations Of Carbamazepine

Epilepsy is a common disease of the nervous system. Currently drug treatment is the major treatment. Carbamazepine is the preferred drug for partial epilepsy and partial epilepsy with secondary generalized seizures, which is a widely used anti-epilepetic drug. In our clinical work, we find there are great individual differences on the efficacy of carbamazepine. Genetic factors, especially the gene polymorphisms of drug-metabolizing enzyme, may play a important role on the differences. Nearly all carbamazepine biatransforms in the liver. The main metabolic enzymes of carbamazepine are CYP3A4 and CYP3A5. In recent years, there are much reseach on the association of CYP3A5 6986A/G gene polymorphism and drug metabolism. These studies indicates that the CYP3A5 genotypes influnce the disposition of various drugs, Which are CYP3A5 substrates. However, the metabolism of some other drugs, which are also CYP3A5 substrates,isn′t impacted by the CYP3A5 genotypes. Presently, there are a few studies on the assosiation between CYP3A5 genetic polymor- phism and the efficacy of carbamazepine. And there is a dispute between studies on this question. The main aim of this project is to study the assosiation of CYP3A5 genetic polymorphism with the serum concentrations of carbamazepine, to further explore whether the CYP3A5 genotypes is a factor of the individual differences of carbamazepine and to provide guide for individualized use of drugs in clinical work.Objective:Investigate the assosiation of genotypes of CYP3A5 6986 and the serum concentrations of carbamazepine to further provide guide for rationalized and individualized use of anti-epileptic drugs.Methods:Collected 84 epileptic patients who took carbamazepine singlely and regularly and observe the efficacy. Use the Dimension? clinical biochemical system and CRBM Flex ? kit to detect the blood concentration of CBZ when the patients have taken carbamazepine for more than one week. Extract DNA from the patients′blood. Then the CYP3A5 6986 polymorphism was analyzed by the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. According to the genotypes, the patients are divided into CYP3A5*1/*1,CYP3A5*1/*3 and CYP3A5*3/*3, namely, CYP3A5 expressor group and CYP3A5 non-expressor group. Compare the efficacy,serum drug concentration, dose-corrected serum concentration, and standardized serum concentration of the two groups ,using Chi-square and T-test. Differences at P < 0.05 were considered significant.Results:Of the 84 cases of epilepisy patients , 3 are CYP3A5*1/*1 genotype, 29 are CYP3A5*1/*3 genotype and 52 are of CYP3A5*3/*3 genotype. Their frequencies are respectively 3.6%, 34.5% and 61.9%. The frenquency of CYP3A5*1 allele is 20.8%, and that of CYP3A5*3 allele is 79.2%. The differences of gender, age, and weight between the CYP3A5 exprssor group and the CYP3A5 non-expressor group were not statistically significant. In the CYP3A5 expressor group, the treatment is effective to 23 patients and ineffective to 9 patients. In the CYP3A5 non-expressor group, the treatment is effective to 37 patients, and ineffecive to 15 patients. Compare the two groups with Chi-square test (χ2=0.05, P=0.943), and the diffrence has no statistical significance. The doseage of carbamazepine of CYP3A5 expressor group is 512.50±128.89 mg, and that of CYP3A5 non-expressor group is 441.35±167.66 mg. The diffference has statistical significance (t=2.054, P=0.043). The doseage of carbamazepine for per kilogram weight of CYP3A5 expressor group is 8.07±2.21mg/kg, and that of CYP3A5 non-expressor group is 6.70±2.53mg/kg. The diffference has statistical significance (t=2.523, P=0.014). The serum drug concentration of CYP3A5 expressor group is 7.03±1.78μg/ml, and that of CYP3A5 non-expressor group is 7.37±2.29μg/ml. The diffference also had no statistical significance (t=-0.699, P=0.487). The dose-corrected serum concentration of CYP3A5 expressor group is 14.08±3.18ng/(ml·mg), and that of CYP3A5 non-expressor group is 18.01±5.62ng/(ml·mg). The diffference has statistical significance(t=-3.607, P=0.001). The standardized serum concentr- ation of CYP3A5 expressor group is 0.90±0.20μg·kg/(ml·mg), and that of the other group is 1.19±0.39μg·kg/(ml·mg). The difference was statistically significant (t=-3.956, P=0.000).Conclusions:The metabolism of carbamazepine is regulated by CYP3A5 gene.CYP3A5 gene polymorphisms affect the serum concentration of carbamazepine. The patients who express CYP3A5 need a larger carbamazepine dose.And the CYP3A5 non-expressors should reduce the dose of carbamazepine to reduce the incidence of adverse reactions and to avoid wastage of drugs.