Investigation On Drug Interaction Between Tacrolimus And Amlodipine And Population Pharmacokinetics Of Tacrolimus In Renal Transplantation Recipients

Post-transplant arterial hypertension (PTAH) affects 60%-85%of all kidney transplant recients. Hypertension is associated with the loss of graft function and an increase of cardiovascular disease and death rate after kidney transplantation. Thus, in order to raise the survival rate of PTAH patients, they should take immunodepressant and antihypertension drugs simultaneously to preserve the renal function and reduce cardiovascular complications.Tacrolimus (FK506) is an calcineurin inhibitor (CNIs) and currently the most widely used as anti-rejection drug in renal transplant recipients. The intra-and inter-individual variability in pharmacokinetics of tacrolimus is significant and the oral bioavailability ranged from 4% to 89%. Treatment concentration range of tacrolimus is 5-20ng/ml Continuous adequate immunosuppression is imperative for maintenance of the graft, whereas overimmunosuppression can lead to serious toxicities. Because tacrolimus has a narrow therapeutic window, it is important that blood tacrolimus concentration should be monitored.Tacrolimus is mainly metabolized via CYP3A in human, which is the major rate-limiting enzyme among metabolism reactions of drug and mainly expresses in the liver and small intestine. The activity of CYP3A5 varies 30-fold in human. These differences lead to different oral bioavailability and clearance rate of drugs. The activity of CYP3A subfamily is mainly due to the activity of CYP3A5 which distribute mostly in the liver and intestine. CYP3A5 expresses differently among individuals. P-glycoprotein (P-gp) is producted by a multidrug resistance gene (MDRI) which plays an important role in the oral absorption of tacrolimus. The P-gp expression is a 2 to 8 fold differences in intestinal biopsy between patients and healthy people. Thus, MDRI gene polymorphism may affect the activity and function of P-gp.Amlodipine, a long-acting dihydropyridine class of calcium-channel blockers, has been shown to improve renal function and control blood pressure in hypertensive renal transplant patients by blocking the action of Ca2+, a second messenger, in angiotensin II and norepinephrine-mediated vasoconstriction, and also by counteracting glomerular afferent arterial systole.Thus, kidney function is protected because glomeruli efferent arteriole is enlarged and glomerular capillaries pressure returnes to normal by amlodipine. Amlodipine is the substrate of CYP3A and P-gp. There may be drug interactions between tacrolimus and amlodipine when used simultaneously. So, it is of great importance for us to study the interaction between them.AIM:1. To investigate the dug-drug interaction between tacrolimus and amlodipine in healthy volunteers in relation to different CYP3A5*3, CYP3A4*1G and MDR1G2677T/C3435T genotype.2. To explore the potential effect of amlodipine on the blood tacrolimus concentration in renal transplant recipients.3. To evaluate quantitatively population pharmacokinetic, inter-and intra-variance of tacrolimus, and to identify the leading impact factors which cause pharmacokinetics variances of tacrolimus orally to guide the individualized tacrolimus administration in adlut renal transplant recipientsMETHODS:1. A PCR-RFLP technique was used for studying the distribution of CYP3A5*3, CYP3A4*1G and MDR1G2677T/C3435T genotypes in Chinese Han people.2. HPLC-MS/MS methods were applied to determine the tacrolimus whole blood samples and amlodipine plasma samples.3. An open, randomized, three-period crossover clinical trial was used to investigate the dug-drug interaction between tacrolimus and amlodipine in healthy volunteers in relation to different CYP3A5*3 and MDR1G2677T/C3435T genotypes.4. The clinical research was developed to observe the concentration effect of amlodipine on tacrolimus.5. Collecting blood tacrolimus concentration data and clinical information of renal transplant recipients with different CYP3 A4* 1G and CYP3A5*3 to establish a population pharmacokinetics of tacrolimus in adult renal transplant recipients. RESULTS:1. The oral clearance of tacrolimus in CYP3A5*1/*1 and CYP3A5*3/*3 group was significantly higher than that in CYP3A5*3/*3,the area under the concentration (AUC) of tacrolimus was less than that in the latter. The AUC of amlodipine in CYP3A5*1/*1 and CYP3A5*3/*3 group was higher than that in CYP3A5*3/*3 group. There was no significant difference in pharmacokinetics of tacrolimus or amlodipine among different MDR1 genotype subjects.2. When tacrolimus and amlodipine were coadministrated with single dose or multiple dose in CYP3A5*1/*1 and CYP3A5*l/*3 subjects, the AUC of tacrolimus in coadministration group was significantly higher than that in tacrolimus alone group, but amlodipine was appeared an opposite result.3. Among CYP3A5*3/*3 subjects, there was no significant difference in the AUC of tacrolimus between tacrolimus plus amlodipine group and tacrolimus alone in single-dose group while significantly higher than that in the former than in the latter in multiple-dose coadministration group. The pharmacokinetics of amlodipine were not changed by coadministration with tacrolimus in single-dose group.4. There was an significant increase in the ratio of blood tacrolimus concentration to dose in hypertensive renal transplant recipients when coadministration tacrolimus with amlodipine and diltiazem for 4 weeks and 6 weeks than that in the baseline.5. Among renal transplant recipients, we found gene polymorphism of CYP3A5*3 and CYP3A4*1G was an important factor leading to apparent clearance (CL/F) variation, and that post operation days (POD) was a factor of column of distribution (V/F) variation. Parameters of PopPK:CL/F is 32.4 L·h-1, V/F is 1700 L. Absorption rate consitant Ka is stable at 3.09 h-1, and individual difference between parameters of CL/F and V/F are 25.9%and 66.7%, respectivelyCONCLUSIONS:1. CYP3A5*3 is an important factor affecting the tacrolimus and amlodipine pharmacokinetics. 2. Among the CYP3A5*1/*1 and CYP3A5*1/*3 subjects, amlodipine raises significantly the whole blood tacrolimus concentration, while tacrolimus increases the oral clearance of amlodipine and decreases the amlodipine concentration level.3. Among the CYP3A5*3/*3 subjects, amlodipine raises the oral clearance of tacrolimus and decrease the blood tacrolimus concentration, while tacrolimus does not significantly affect the pharmacokinetics of amlodipine.4. Amlodipine used in renal transplant recipients may increase the concentration of tacrolimus.5. CYP3A4*1G, CYP3A5*3 and post operation days (POD) are the main factor resulting the pharmacokinetic intra-and inter-individual variances of tacrolimus.6. The population pharmacokinetic model of tacrolimus in renal transplant recipients can provides the scientific basis for the individualized tacrolimus therapy in Chinese adult renal transplant recipients.