Liu Bing-Yang, Chen Wen-Qian, Chen Zhi-Gao, Huang Jie, Liao Zhong-Kai, Liu Qing, Zheng Zhe, Song Yun-Hu, Wang Wei, Hu Sheng-Shou
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, No. 167 North Lishi Road, Xicheng District, Beijing, 100037, China.
Fuwai Central China Cardiovascular Hospital, Zhengzhou, 450000, China.
Eur J Drug Metab Pharmacokinet. 2019 Dec;44(6):771-776. doi: 10.1007/s13318-019-00563-x.
Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients.
We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality.
In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A51/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314).
CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.
有效管理免疫抑制剂对改善心脏移植受者的预后极为重要。我们旨在研究细胞色素P450（CYP）3A5（rs776746）单核苷酸多态性（SNP）对中国心脏移植受者血清他克莫司浓度/剂量（C/D，每毫克/千克纳克/毫升）及长期预后的影响。
我们检测了2005年8月至2012年7月期间连续的203例中国心脏移植受者的CYP3A5 SNP，其中55例接受基于他克莫司的免疫抑制治疗的患者纳入本研究。常规计算移植后1、3、6、12、24和36个月时的他克莫司C/D。在心脏移植后1、3和6个月进行X线引导下的心内膜心肌活检（EMB）以评估急性排斥反应程度。然后对所有参与者进行年度随访直至2018年5月。设计的主要终点是全因死亡率。
在55例心脏移植受者（43例男性和12例女性）中，CYP3A5非表达者（CYP3A5*3/3，n = 40）在所有时间点的他克莫司C/D均显著高于表达者（CYP3A51/*3，n = 15）（P < 0.001）。卡方检验显示心脏移植后6个月内两组经EMB证实的急性排斥反应无显著差异。中位随访期为94.7个月，8例患者死亡。Kaplan-Meier分析显示CYP3A5表达者的死亡率倾向于高于非表达者（20%对12.5%，对数秩检验：P = 0.314）。
CYP3A5 SNP影响中国心脏移植受者的他克莫司药代动力学，非表达者的他克莫司C/D更高。此外，表达者的长期预后倾向于比非表达者更差。
