CLINICAL IMMUNOSUPPRESSION - KIDNEY EARLY

C. Wang¹, L. Liu², J. Fei¹, J. Li³, S. Deng¹, J. Li¹, Q. Fu¹, X. Yuan², L. Teng^1
1Organ Transplant Center, The First Affiliated Hosptial, Sun Yat-sen University, Guangzhou/CHINA, ²Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou/CHINA, ³Institute Of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou/CHINA

Body: Introduction CYP3A5 and MDR1 play roles in the absorption and metabolism of tacrolimus. Diltiazem can increase tacrolimus concentration by drug interaction. The present study demonstrated the effect of CYP3A5 and MDR1 genetic polymorphism on tacrolimus pharmacokinetics in response to accompanying diltiazem in kidney transplant (KTx) recipients. Methods A total of 144 KTx recipients who received tac + MMF + steroids immunosuppressive therapy, were divided into two groups. Forty-eight patients who received diltiazem (30 mg tid) were assigned to diltiazem group, and 96 patients without diltiazem therapy were assigned to control group. CYP3A5*3 genotype and MDR1 genotype (1236C>T, 2677G>T/A, 3435C>T) were examined. CYP3A5 expresser was defined as patients with CYP3A5*1/1 and CYP3A5*1/3 genotypes, and CYP3A5 non-expresser was defined as patients with CYP3A5*3/3 genotype. Trough concentration of tacrolimus at day 7 after KTx was examined in all patients. Fourteen days after continuous tacrolimus administration, the pharmacokinetics of tacrolimus was examined in diltiazem group (n=30) and control group (n=36). Dose and body weight adjusted trough concentration of tacrolimus (C₀) at day 7, and the latter Cmax and AUC_0-12h were compared depending on the use of diltiazem, and CYP3A5 or MDR1 genotype. Results In control group without diltiazem, CYP3A5 expressers presented lower C₀ at day 7 than non-expressers (71 ± 33.4 vs 130 ± 75.5 ng/ml/mg/kg, p<0.05). CYP3A5 expressers showed lower AUC_0-12h than non-expressers (1545 ± 1008.1 vs 2550 ± 2727.6 ng/ml·h/mg/kg, p<0.05). In CYP3A5 expressers, diltiazem dramatically increased C₀ at day 7 by 48.7%, when diltiazem group was compared to control group (105 ± 50.9 vs 71 ± 33.4 ng/ml/mg/kg, p<0.05). However, this phenomenon didn’t happen in CYP3A5 non-expressers. Meanwhile, compared to control group, diltiazem group presented significantly increased Cmax and AUC_0-12h, in CYP3A5 expressers by 31.7% and 38.2%, andin CYP3A5 non-expressers by 17.2% and 18.5%, respectively. CYP3A5 expressers showed higher increasing extent than non-expressers. In control group, no significant difference in pharmacokinetic parameters of tacrolimus was observed in patients with different MDR1 genotype. Moreover, in the groups with different MDR1 genotype, similar increasing extent in pharmacokinetic parameters was observed when the patients with diltiazem were compared to the control. Conclusion In kidney transplant patients, CYP3A5*3 genotype has evident effect on tacrolimus pharmacokinetics. Furthermore, it affects the response of tacrolimus to metabolic inhibitory diltiazem. This study indicates the individualization of tacrolimus therapy in patients with different CYP3A5*3 genotype, especially when diltiazem or other drugs which may affect tacrolimus pharmacokinetics are concurrently used.

Disclosure: All authors have declared no conflicts of interest.