Park Jangho, Lee Kwang-Woong, Oh Seung Cheol, Park Min Young, Lee Jeong-Moo, Hong Su Young, Hong Suk Kyun, Choi YoungRok, Yi Nam-Joon, Suh Kyung-Suk
Department of Surgery, College of Medicine, Seoul National University, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
Hepatol Int. 2023 Feb;17(1):262-270. doi: 10.1007/s12072-022-10401-z. Epub 2022 Aug 16.
The effects of multidrug resistance-1 (MDR1), ABCC2, and P450 oxidoreductase (POR)28 gene polymorphisms on tacrolimus metabolism following a switch to once-daily dosing have not been elucidated. We investigated the effects of recipient and donor CYP3A5, MDR1, ABCC2, and POR28 polymorphisms on tacrolimus pharmacokinetics following a switch to once-daily tacrolimus dosing.
Eighty-seven liver transplant recipients who were switched from twice- to once-daily tacrolimus dosing following living-donor liver transplantation and 81 matched donors were genotyped for CYP3A5, MDR1 (1236C>T, 2677G>T/A, and 3435C>T), ABCC2 (-24C>T, 1249G>A, and 3972C>T), and POR*28. Tacrolimus dose-adjusted trough levels (C0/dose) before and after the switch were determined and calculated based on past medical records. Recipients were divided into two groups, one group constituted of 38 patients with a C0/dose decrease of less than 30% following conversion (group 1) and the other constituted of 49 patients with a C0/dose decrease of ≥ 30% (group 2).
CYP3A5 *1/*3 and *3/*3 were more frequent in recipients in group 1 (60.5% vs. 36.8%), while CYP3A5 *1/*1 was more frequent in group 2 (59.2% vs. 32.7%) (p = 0.016). The proportions of donor ABCC2 1249G>A genotypes AA and AG were higher in group 2 than in group 1 (20.4% vs. 5.3%; p = 0.042).
Recipient CYP3A5 polymorphism and donor ABCC2 1249G>A polymorphism affected tacrolimus pharmacokinetics following the switch to once-daily dosing. Dose adjustment to maintain therapeutic tacrolimus levels following the switch to once-daily dosing should be considered based on polymorphisms in both the recipient and donor.
多药耐药蛋白1（MDR1）、ABCC2和细胞色素P450氧化还原酶（POR）28基因多态性对转换为每日一次给药后他克莫司代谢的影响尚未阐明。我们研究了受者和供者的细胞色素P450 3A5（CYP3A5）、MDR1、ABCC2和POR28基因多态性对转换为每日一次他克莫司给药后他克莫司药代动力学的影响。
对87例活体肝移植后从每日两次他克莫司给药转换为每日一次给药的肝移植受者和81例匹配的供者进行CYP3A5、MDR1（1236C>T、2677G>T/A和3435C>T）、ABCC2（-24C>T、1249G>A和3972C>T）以及POR*28基因分型。根据既往病历确定并计算转换前后他克莫司剂量调整后的谷浓度（C0/剂量）。将受者分为两组，一组由38例转换后C0/剂量降低小于30%的患者组成（第1组），另一组由49例C0/剂量降低≥30%的患者组成（第2组）。
第1组受者中CYP3A5 *1/3和3/*3更为常见（60.5%对36.8%），而第2组中CYP3A5 *1/*1更为常见（59.2%对32.7%）（p = 0.016）。第2组供者ABCC2 1249G>A基因型AA和AG的比例高于第1组（20.4%对5.3%；p = 0.042）。
受者CYP3A5基因多态性和供者ABCC2 1249G>A基因多态性影响转换为每日一次给药后他克莫司的药代动力学。转换为每日一次给药后，应根据受者和供者的基因多态性考虑调整剂量以维持他克莫司的治疗水平。
