Cyp3a4 In Chinese Han People With Epilepsy / 3 A5 Family Gene Polymorphism With Carbamazepine Concentration And Effect Of The Relevance Of Research

Part1:Single nucleotide polymorphisms and genotype frequencies of CYP3A4*1G, CYP3A5*3, CYP3A4*18/*19in Han Chinese epileptic patientsObjective To explore the distribution and genotype frequencies of CYP3A4*1G, CYP3A5*3, CYP3A4*18/*19in Han Chinese epileptic patients with carbamazepine(CBZ)-therapy.Materials and Methods The CYP3A4*1G,CYP3A5*3, CYP3A4*18/*19genotype was determined by ligase detection reaction-Polymerase Chain Reaction (LDR-PCR) in247Han Chinese epileptic patients with carbamazepine (CBZ)-therapy.Results Ten patients(4.05%) were AA allele of CYP3A4*1G,92(37.25%) were AG allele and145(58.70%) were GG allele. A allele frequencies were22.67%, while G allele frequencies were77.33%. Twenty-three patients (9.31%) were AA allele of CYP3A5*3,109patients (44.13%) were AG allele, and115patients (46.56%) were GG allele. And A allele frequencies were31.38%, G allele frequencies were68.62%. All patients were CC allele of CYP3A4*18/*19.Conclusion The genotype frequencies of CYP3A4*1G and CYP3A5*3in Han Chinese epileptic patients is similar to it in other Asian population. Part2:Effect of CYP3A4*1G, CYP3A5*3genotype on serum carbamazepine concentrations at steady-state in Han Chinese epileptic patientsObjective The present study aimed to assess the effect of CYP3A4*1G, CYP3A5*3genotype on serum CBZ concentrations at steady-state.Materials and Methods The serum concentrations of CBZ in247Han Chinese epileptic patients with CBZ-therapy and their CYP3A4*1G, CYP3A5*3genotype was determined by LDR-PCR method. Results Among all247Han Chinese epileptic patients(total group), the normalized concentrations of CBZ were0.23±0.065μg·kg·(ml·g)-1) for CYP3A4*1G AA allele,0.25±0.065μg·kg·(ml·g)-1) for AG allele and0.28±0.074μg·kg·(ml·g)-1) for GG allele. There was a significant difference between these three different genotypes (P=0.005).And the normalized concentrations of both AA allele and AG allele were lower than those of GG allele, and the difference was statistical significance(P<0.05). Although the normalized concentrations of AA allele were lower than those of AG allele, there was no significant difference between them. They were0.23±0.066μg·kg·(ml·g)-1) for CYP3A5*3AA allele,0.24±0.053μg·kg·(ml·g)-1) for AG allele and0.31±0.073μg·kg·(ml·g)-1) for GG allele. There was a significant difference between these three different genotypes (P<0.0001). The normalized concentrations of CBZ were significant higher in GG allele. But there was no significant difference between AA allele and AG allele. The same result was found in monotherapy group but not in add-on group.Conclusion The CYP3A4*1G, CYP3A5*3genotype affected the CBZ concentrations in Han Chinese patients that the normalized concentrations of CBZ in patients of GG allele were higher. And it is a possible factor that may contribute to inter-individual variability in CBZ disposition in Han Chinese epileptic patients. Part3:Influence of CYP3A4*1G, CYP3A5*3genotype on carbamazepine efficacy in Han Chinese epileptic patientsObjective To investigate the relationship between the CYP3A4*1G CYP3A5*3genotype and the CBZ treatment outcome in Han Chinese epileptic patients.Materials and Methods The CYP3A4*1G CYP3A5*3genotype was determined in245Han Chinese epileptic patients with CBZ-therapy (including total group, monotherapy group and add-on group). Then they were also classified by phenotype of CYP3A4*1G CYP3A5*3gene as the hypermetabolism group (AA allele and AG allele) and the hypometabolism group (GG allele). The efficacy at6months after therapy were classified as markedly effective (the reduction of seizure frequency>75%), effective (50%<the reduction of seizure frequency<75%) and ineffective (the reduction of seizure frequency<50%).Results In total group, both the normalized concentrations (0.25±0.067μg·kg·(ml·g)-1) and the markedly effective rates (36%) of CYP3A4*1G hypermetabolism group, were significant higher than the hypometabolism group (0.28±0.080μg·kg·(ml·g)-1)(48.97%)(P<0.05). While the ineffective rates of hypermetabolism group (25%) were significant higher than the hypometabolism group (18.62%)(P<0.05). The same result was found in monotherapy group but not in add-on group. The markedly effective rates of CYP3A5*3GG allele were63.48%,60.76%,69.44%, in total group, monotherapy group, and add-on group, which were significant higher than those in AG allele(30.28%,36.14%,38.16%) and AA allele(4.76%,7.69%,38.16%). And it showed in Logistic Regression that the CYP3A4*1G genotype had no influence on the CBZ efficacy. But the CYP3A5*3genotype was possible factor that may contribute to inter-individual variability in CBZ efficacy in Han Chinese epileptic patients in Logistic Regression analysis.Conclusion The CYP3A5*3genotype had influence on the carbamazepine concentrations and efficacy. The normalized concentrations and markedly effective rates of CYP3A5*3GG allele were significant higher.