Genetic Polymorphism Optimize The Drug Regimens And Influence Population Pharmacokinetics Of Tacrolimus In Liver Transplant Patients

OBJECTIVE:1. Study the genotype distribution of CYP2C9, CYP2C19, and CYP3A5 in Chinese adult liver transplant donors and recipients, and analyze differences between the recipients and healthy population.2. Base on genotype combinations of donors and recipients to optimize drug regimen after liver transplantation.3. Establish the population pharmacokinetic model of tacrolimus in Chinese adult orthotopic liver transplant patients, and examine the impact of gene polymorphism and demographic characteristics on tacrolimus pharmacokinetics for providing a reliable theoretical basis in individual medical.METHODS:1. Gene polymorphism detection of liver transplant donors and recipients89 Chinese orthotopic liver transplant patients were selected in the study. The CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3 polymorphism of liver transplant donors and recipients, and multidrug resistance gene 1(MDR1)C3435T, MDR1 G2677T/A polymorphism of the recipients were detected by polymerase chain reaction-restriction fragment length polymorphism. Difference was compared by using Mann-Whitney U test.2. Optimize drug regimens by integrating gene polymorphism of liver transplant donors and recipientsAccording to the number of negative allele in donor and recipient genotype combination, the CYP metabolized capability of recipients after liver transplantation were roughly classified into three types: Extensive metabolizer(EM), Intermediate metabolizer(IM) and Poor metabolizer(PM). Considering the relationship between CYP metabolized capability and clinical efficacy, we optimized the dosage regimens for recipients.3. Influence of gene polymorphisms on tacrolimus population pharmacokineticThe tacrolimus concentration in whole blood was measured by microparticle enz yme immunoassay. Nonlinear mixed-effects model was used in establishing tacrolimus population pharmacokinetic model. The infactors of tacrolimus pharmacokinetics were examined during the modeling procession. The final model was validated.RESULTS:1. The result of gene polymorphism detectionIn this study, there was no CYP2C9*2/*2, CYP2C9*3/*3 and CYP2C19*2 in the recipient and donor population. The CYP2C19*3 frequency in recipients and donors were 23.60% and 26.97%, respectively. CYP3A5*3 frequency in recipients was high as 74.72%. Compared with healthy people, CYP2C9*2 and CYP2C19*3 frequencies were higher in recipients, and the CYP2C19*2 allele frequency was lower. There was no statistic difference in CYP2C9*3 and CYP3A5*3 frequencies between recipients and healthy population.In recipients population, numbers of MDR1 G2677T/A GG genotype, GA genotype, GT genotype, AA genotype, TT genotype, and TA genotype were respectively 20(22.47%), 9(10.11%), 32(35.96%), 6(6.74%), 15(16.85%) and 7(7.87%); numbers of MDR1 C3435 T CC genotype, CT genotype and TT genotype were 37(41.57%), 41(46.07%) and 11(12.36%), respectively. Genotype frequencies of MDR1 G2677T/A and C3435 T in recipients were consistent with domestic healthy population.2. Optimize drug regimens by integrating gene polymorphism of liver transplant donors and recipientsIn the study, most recipients were still CYP2C9 EM after transplantation. Drugs metabolized by CYP2C9 enzyme were recommended standard dose regimen. Almost recipients were CYP2C19 EM and IM. Regimen regulation was also based on efficacy characteristics of each drug, excepting genetype of donor and recipient. 2/3recipients were CYP3A5 EM or IM. Dosage regimens of CYP3A5 metabolic drugs for these patients were recommended standard dose regimen; 1/3 recipients were CYP3A5 PM. Dosage regimens for them should be diminished.3. Influence of gene polymorphisms on tacrolimus population pharmacokineticTacrolimus population pharmacokinetic model was established by analyzing tacrolimus blood concentration data in one compartment model. In final model,apparent clearance(CL/F) and apparent volume of distribution(Vd/F) of tacrolimus were 17.7 L/h, and 213 L.There were 6 factors had significant effects on CL/F including postoperative time, blood urea nitrogen, alkaline phosphatase, total bilirubin, hemoglobin and recipients CYP3A5 genotype. For a Vd/F, significant effect factors were postoperative period, total bilirubin, hemoglobin and total protein. CL/F of tacrolimus in recipients with CYP3A5*1 was almost 1.83 times higher than those who with CYP3A5*3/*3.CONCLUSION:1. In the liver transplant population, the CYP3A5*3 mutation frequency was high,and CYP2C19*3 allele frequency was significant difference to healthy people.Therefore, in order to optimize regimens based on donors and recipients genotype,detections of CYP2C19*3 and CYP3A5*3 genotype were recommended for liver recipients and donors.2. Most recipients were received liver with different CYP genetic background. Based on CYP2C9, CYP2C19, CYP3A5 genotype combination of donors and recipients,drugs metabolized by CYP2C9 could be used the standard regimen, while drugs metabolized by CYP2C19 and CYP3A5 should be adjusted.3. In the population pharmacokinetic model of tacrolimus in 89 Chinese adult orthotopic liver transplant patients, typical CL/F and Vd/F of tacrolimus were 17.7L/h and 213 L.There were 6 factors had significant effects on CL/F including postoperative time, blood urea nitrogen, alkaline phosphatase, total bilirubin,hemoglobin and recipients CYP3A5 genotype. For Vd/F, significant effect factors were postoperative period, total bilirubin, hemoglobin and total protein. These indexes should be monitored to rationally adjust the dose. MDR1 2677G>T/A 、3435C>T gene of recipients and CYP3A5*3 gene of donors were not significant effect factors for the tacrolimus pharmaconetics, while CYP3A5*3 gene of recipients was significant effect factor.What’s more, CL/F of tacrolimus in recipients with CYP3A5*1 was almost 1.83 times higher than those who with CYP3A5*3/*3, which indicated reducing tacrolimus dosage for the latters.