Jianyu Liu1, Dexi Chen2, Bo Yao3, Ge Guan1, Chao Liu1, Xinmin Jin1, Xin Wang1, Peng Liu1, Yandong Sun1, Yunjin Zang4. 1. Institute of Transplantation Science, Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China. 2. Institute of Hepatology, Beijing You'An Hospital, Capital Medical University, Beijing, China. 3. Department of Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China. 4. Institute of Transplantation Science, Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China. Electronic address: zyjnsfc@126.com.
Abstract
BACKGROUND: For liver transplant (LT) recipients, the liver CYP3A5 metabolic enzymes are determined by the donor's genes, whereas the intestinal enzymes are encoded by the recipient's genes. This combinational form confuses the metabolism of tacrolimus (Tac) in vivo. This retrospective study was conducted to investigate the combined effects of donor-recipient CYP3A5 genotype on tacrolimus pharmacokinetics in Chinese LT adult patients. METHODS: Three hundred seventy-three LT patients from two Chinese organ transplant centers were enrolled, and both recipients and donors were genotyped for CYP3A5. Patients were divided into four groups (RNDN, REDN, RNDE, REDE) according to CYP3A5*3 allele expressers (E) and non-expressers (N) in recipients (R) and donors (D). The dose-adjusted trough levels (C/D ratio) of tacrolimus were assessed for six months among the four groups. Multiple linear regression analysis was performed to assess the effects of the CYP3A5 genotype and several clinical variables on the C/D ratio. RESULTS: The RNDN group consistently had the largest C/D ratio throughout the entire study period, whereas the REDE group had the smallest C/D ratio, and the REDN/RNDE group had an intermediate (RNDN > REDN/RNDE > REDE) ratio. The C/D ratio in the RNDN and RNDE groups was higher than that in the REDN and REDE groups within three months, respectively; the ratio in the RNDN group was higher than that in the RNDE group, and the ratio in the REDN group was higher than that in the REDE group at six months. The effect of the donor CYP3A5 genotype on C/D values was observed throughout the timeline, and the recipient's genetics correlated only in the first three months. Among non-genetic factors, hemoglobin (HGB) and albumin (ALB) were correlated with Tac C/D values at a few time points. CONCLUSIONS: To predict the initial dose of tacrolimus in LT patients, both donor and recipient CYP3A5 genotypes must be taken into account; during the maintenance phase of targeted blood concentration, the donor's CYP3A5 genotype may be of prime importance, especially at three months after transplantation.
BACKGROUND: For liver transplant (LT) recipients, the liver CYP3A5 metabolic enzymes are determined by the donor's genes, whereas the intestinal enzymes are encoded by the recipient's genes. This combinational form confuses the metabolism of tacrolimus (Tac) in vivo. This retrospective study was conducted to investigate the combined effects of donor-recipient CYP3A5 genotype on tacrolimus pharmacokinetics in Chinese LT adult patients. METHODS: Three hundred seventy-three LT patients from two Chinese organ transplant centers were enrolled, and both recipients and donors were genotyped for CYP3A5. Patients were divided into four groups (RNDN, REDN, RNDE, REDE) according to CYP3A5*3 allele expressers (E) and non-expressers (N) in recipients (R) and donors (D). The dose-adjusted trough levels (C/D ratio) of tacrolimus were assessed for six months among the four groups. Multiple linear regression analysis was performed to assess the effects of the CYP3A5 genotype and several clinical variables on the C/D ratio. RESULTS: The RNDN group consistently had the largest C/D ratio throughout the entire study period, whereas the REDE group had the smallest C/D ratio, and the REDN/RNDE group had an intermediate (RNDN > REDN/RNDE > REDE) ratio. The C/D ratio in the RNDN and RNDE groups was higher than that in the REDN and REDE groups within three months, respectively; the ratio in the RNDN group was higher than that in the RNDE group, and the ratio in the REDN group was higher than that in the REDE group at six months. The effect of the donorCYP3A5 genotype on C/D values was observed throughout the timeline, and the recipient's genetics correlated only in the first three months. Among non-genetic factors, hemoglobin (HGB) and albumin (ALB) were correlated with Tac C/D values at a few time points. CONCLUSIONS: To predict the initial dose of tacrolimus in LT patients, both donor and recipient CYP3A5 genotypes must be taken into account; during the maintenance phase of targeted blood concentration, the donor's CYP3A5 genotype may be of prime importance, especially at three months after transplantation.