Influencing Factors Of Plasma Tacrolimus Concentration Of Recipients With Post Renal Transplant Hypertension And The Population Pharmacokinetics Of Tacrolimus

Objectives:(1) To investigate CYP3A4*1G (20230 G> A) and CYP3A5*3 (6986 A> G) gene polymorphism of recipients with post renal transplant hypertension, and study the affect of polymorphism on Concentration/Dose of Tacrolimus. (2) Investigate the affect of Diltiazem on Concentration/Dose of Tacrolimus. (3) Develop a population pharmacokinetics model for Tacrolimus in Chinese renal transplant recipients.Methods:(1) 110 recipients with post renal transplant hypertension were selected randomly from 300 renal transplant patients. used polymerase restrictive fragment length polymorphism (PCR-RFLP) and PCR sequencing PCR technique to detect the CYP3A4*1G and CYP3A5*3 gene polymorphism.(2) 70 recipients with post renal transplant hypertension were randomized from the 110 patients, and determined their Tacrolimus trough level (Co) by Microparticle Enzyme Immunoassay (MEIA) after a treatment with Tacrolimus at least 1 week. Classified the patients into three groups according to the gene polymorphism of CYP3A5*3 and CYP3A4*1G, and analyzed the affect of gene polymerphism on Tacrolimus Concentration/Dose by one-factor analysis of variance analysis.(3) 60 recipients with post renal transplant hypertension were randomized from the 110 patients. used own control method to analyze Tacrolimus Concentration/Dose before and after the treatment of Diltiazem. Tacrolimus trough level was determined by MEIA, and the data was analysed by paired t-test.(4) 188 renal transplant patients were randomized from the 300 patients, and 525 data of Tacrolimus plasma sample concentrations were collected, as well as the demography, biochemical indicator, incorporated medicine and genotype (CYP3A5*3 and CYP3A4*1G) of the patients. Nonlinear mixed-effects modelling was used to evaluate the data using NONMEM, and developed a population pharmacokinetics model for Tacrolimus. Results:(1) Among the 110 recipients with post renal transplant hypertension, CYP3A4*1G (20230 G> A) genotypic frequency was *1*1G (48.18%),*1*1 (47.27%) and*1G*1G (4.55%), allele frequency was G (71.36%) and A (28.64%); CYP3A5*3 (6986 A> G) genotypic frequency was*1*3 (50.00%),*3*3 (44.55%) and*1*1 (5.45%), allele frequency was A (30.45%) and G (69.55%).(2) Among the recipients with post renal transplant hypertension, the Tacrolimus Concentration/Dose of CYP3A4*1*1 group was significantly higher than the CYP3A4*1*1G and CYP3A4*1G*1G group (p< 0.05); While CYP3A5*3*3 group was significantly higher than the CYP3A5*1*1 and CYP3A5*1*3 group (p< 0.05). In order to get similar plasma Tacrolimus concentration, CYP3A4*1*1G and CYP3A4*1G*1G patients required higher dosage of Tacrolimus than the CYP3A4*1*1 patients, CYP3A5*1*1 and CYP3A5*1*3 patients required higher dosage of Tacrolimus than the CYP3A5*3*3 patients.(3) After the treatment of Diltiazem, the Tacrolimus Concentration/ Dose of renal transplant patients with hypertension was significantly increased (p< 0.05).(4) A 1-compartment pharmacokinetics model with first-order absorption after oral administration adequately discribed the data. Typical clearance (CL/F), distribution volume (V/F) and Ka was 30.1L·h-1,3420L and 3.09h-1 respectively. In the final model, genotype of CYP3A5*3, Hemoglobin (HGB) and Direct Bilirubin (DBIL) showed significant influfence on CL/F, and postoperative days (POD) showed significant influfence on V/F.Conclusions:(1) In recipients with post renal transplant hypertens-ion, allele A frequency of CYP3A4* 1G (20230 G> A) was 28.64%, and allele G frequency of CYP3A5*3 (6986 A> G) was 69.55%. The distribution of both CYP3A4*1G and CYP3A5*3 were in Hardy-Weinberg equilibrium (all P> 0.05).(2) The Tacrolimus Concentration/Dose was significantly associated with the CYP3A4*1G and CYP3A5*3 gene polymorphism.(3) Tacrolimus Concentration/Dose of renal transplant patients with hypertension would be increased significantly by Diltiazem. (4) Tacrolimus CL/F of renal transplant patients carrying CYP3A5*3*3 was the lowest, and patients carrying CYP3A5*1*1 was lower than the CYP3A5*1*3 genotype patients. Tacrolimus CL/F decreased with increasing DBIL, and also decreased with increasing HGB. Tacrolimus V/F increased with extending POD.