The Influence Of CYP3A5/3A4 SNPs To The Pharmacokinetics Of Tacrolimus In Pediatric Liver Transplantation

Objective:To investigate the characteristics of plasma concentration,dose,concentration /dose ratio of tacrolimus in pediatric living donor liver transplantation in the first 3month post-transplantation,and to study the effects of CYP3A5 * 3 and CYP3A4 *18B gene polymorphism of both recipients and donors to tacrolimus drug metabolism,and analysis the influencing factors which affect Tac metabolism.On the whole,to provide a reasonable reference for clinically determination of the individualized administration of tacrolimus.Methods:1.The analysis of the pharmacokinetic characteristics of tacrolimus in the early post-transplantation period of recipients: There were eighty pediatric recipients selected according to the criteria of inclusion and exclusion.The weight,dose and the combined medication of tacrolimus,liver and kidney function indicators of the pediatric recipients were monitored and recorded regularly on the 1th,3th,5th,7th,14 th and the second and third months post-transplantation.The concentration was detected by ELISA,and the polymorphism of CYP3A5*3 and CYP3A4*18B were detected by DNA direct sequencing.Analysis of Tac dose,plasma concentration and C₀/D characteristics and differences between individuals.2.The influences of CYP3A5*3?rs776746?SNPs of both recipients and donors of pediatric living donor liver transplantation to the pharmacokinetics of tacrolimus: The polymorphism of CYP3A5*3 were detected by DNA direct sequencing.The pharmacological characteristics of Tac were compared between the different groups according to CYP3A5*3 genotypes of recipients,donors and both recipients and donors.Multivariate stepwise regression analysis was performed with The C₀/D as the dependent variable,the rest of the physiological factors and the CYP3A5*3 gene polymorphism as the independent variables.The influencing factors of tacrolimus C₀/D in the liver transplant recipients were investigated.2.The influences of CYP3A4*18B?rs12333983?SNPs of both recipients and donors of pediatric living donor liver transplantation to the pharmacokinetics of tacrolimus: The polymorphism of CYP3A4*18B were detected by DNA direct sequencing.The pharmacological characteristics of Tac were compared between the different groups according to CYP3A4*18B genotypes of recipients,donors and both recipients and donors.Multivariate stepwise regression analysis was performed withThe C₀/D as the dependent variable,the rest of the physiological factors and the CYP3A4*18B gene polymorphism as the independent variables.The influencing factors of tacrolimus C₀/D in the liver transplant recipients were investigated.Results:1.The initial dose of Tac was?0.10±0.03?mg.kg^-1.d^-1,the dose of Tac was increasing during the first 7 days post-transplantation,and the maximum dose was?0.21±0.09?mg.kg^-1.d^-1 at second month?0.21 ± 0.09?mg.kg^-1.d^-1,while the Tac dose decreased slightly at second month.Less than 50% of recipients could reach the target concentration range during the first month,only 28.75% of recipients could reach the target concentration range at first month,and 65.0% of the recipients below the target concentration.52.5% and 57.5% of recipients were able to achieve the target plasma concentration at second and third month.2.The incidence of CYP3A5 *1 allele was 31.9% and CYP3A5*3 was 68.1%among the eighty pediatric rirecipients.The relationship of D,C₀,C₀/D among CYP3A5*1*1,CYP3A5*1*3 and CYP3A5*3*3 groups was : *1*1> *1*3> *3*3,*3*3> *1*3>*1*1,*3*3> *1*3>*1*1.The dose of Tac in EX-R/EX-D group and EX-R/NEX-D group was higher than that in NEX-R/NEX-D group during the first 3month post-transplantation.The dose of Tac in NEX-R/NEX-D was significantly higher than that of EX-R/EX-D group and EX-R/NEX-D group.The C₀/D of EX-R/EX-D group and EX-R/NEX-D group were significantly lower than those of NEX-R/NEX-D group.3.The polymorphism of CYP3A5*3 had a significant effect on the metabolism of Tac during the first 3 month post-transplantation?P<0.05?,accounting for 38.95%,while the CYP3A5*3 genotype of donors had a major effect of 31.83%?P=0.003?and the CYP3A5*3 genotype of recipients,accounting for 7.12%?P=0.024?.4.The incidence of CYP3A4*18B allele was 29.38% and the incidence of CYP3A4*1 was 70.62%among the eighty pediatric rirecipients.The relationship of D,C₀,C₀/D among CYP3A4*18B*18B,CYP3A4*1*18B and CYP3A4*1*1 groups was: *18B*18B>*1*18B>*1*1,*1*1>*1*18B>*18B*18B,*1*1>*1*18B>*18B*18B.The dose of Tac in EX-R/EX-D group was statistically higher than that in NEX-R/NEX-D group during the first 2 month post-transplantation.The C₀/D of NEX-R/NEX-D group was significantly higher than that of EX-R/EX-D group and EX-R/NEX-D group during the first month.Only the CYP3A4*18B genotype of recipients had a significant effect on Tac metabolism?P=0.046?,accounting for13.66%,while the donor CYP3A4*18B genotype was not the main influencing factorof Tac metabolism?P> 0.05?.Conclusions:1.The differences between individuals was large,and the fluctuation range of C₀/D was large in the first month post-transplantation,and the C₀/D was in a stable stage during the after two month.And only relying on TDM and clinical symptoms to adjust the dose was difficult to achieve satisfactory immunosuppressive effect,it is necessary using pharmacogenomics to determine individualized regimens.2.The incidence of CYP3A5 *1 allele was 31.9% and CYP3A5*3 was 68.1%among the eighty pediatric recipients.The dose of Tac of recipients who carried CYP3A5*1 was significantly higher than that of CYP3A5*3*3 recipients.The gene polymorphism of CYP3A5*3 can be helpful to predict the dose of Tac.The dose of Tac which the recipients need is closely related to the polymorphism of CYP3A5*3genotype.3.Preoperative detection of CYP3A5*3 genotypes of donors can predict the metabolism of Tac and provide a reliable reference for the individual administration of Tac in pediatric living donor liver transplantation recipients.4.The incidence of CYP3A4*18B allele was 29.38% and the incidence of CYP3A4*1 was 70.62% among the eighty pediatric rirecipients.The dose of Tac of recipients who carried CYP3A4*18B was significantly higher than that of CYP3A4*1*1 recipients.Only the CYP3A4*18B genotype of recipients had a significant effect on Tac metabolism,while the donor CYP3A4*18B genotype was not the main influencing factor of Tac metabolism.5.Preoperative detection of CYP3A4*18B genotypes of recipients can predict the metabolism of Tac and provide a reliable reference for the individual administration.