Zhang Jing, Dai Ying, Liu Zhihong, Zhang Minxin, Li Chen, Chen Dingxiong, Song Hongtao
*Department of Pharmacy, Fuzhou General Hospital of Nanjing Command PLA, Fuzhou, China; †Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; and ‡Institute for Chemical Drug Control, Fujian Institute for Food and Drug Quality Control, Fuzhou, China.
Ther Drug Monit. 2017 Aug;39(4):406-411. doi: 10.1097/FTD.0000000000000415.
Sirolimus is a promising immunosuppressive drug for preventing the rejection of organ transplants. However, inter-individual variability in sirolimus pharmacokinetics causes adverse drug reactions, compromising therapeutic efficacy. Sirolimus is primarily metabolized by cytochrome CYP3A4 and CYP3A5. This study aimed to clarify the effect of CYP3A genetic polymorphisms, including the CYP3A41G and CYP3A53 polymorphisms, on the pharmacokinetics of sirolimus.
Thirty-one healthy Chinese volunteers were included in this study. Their genotypes were determined using the Sequenom MassARRAY iPLEX platform, and blood sirolimus concentrations at different time points were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using WinNonlin version 5.2 software.
The allele frequencies of CYP3A41G and CYP3A53 were 25.8% and 71.0%, respectively. In CYP3A41G carriers (n = 13), the area under the curve AUC0-144, AUC0-∞, and Cmax were significantly lower (P < 0.05) than CYP3A41/*1 homozygous subjects (n = 18). Briefly, the AUC0-144, AUC0-∞, and Cmax of *1G/*1G carrier were 315.2 ± 91.5, 372.0 ± 108.2, and 10.2 ± 1.6 ng/mL, respectively, and those of *1/1 G1/1 G carrier were 440.8 ± 130.6, 537.4 ± 167.5, and 13.7 ± 4.3, respectively, whereas those of CYP3A41/*1 homozygous subjects were 540.2 ± 150.6, 626.6 ± 166.9, and 19.8 ± 7.5 ng/mL, respectively. In CYP3A5-nonexpressing subjects (*3/*3 homozygous carriers, n = 15), the AUC0-144 and Cmax were 549.6 ± 137.9 and 19.9 ± 7.9 ng/mL, respectively, and were significantly higher (P < 0.05) than the values in CYP3A5-expressing subjects (*1/*1homozygous carrier, n = 2; 314.2 ± 129.3 and 10.3 ± 2.2 ng/mL; *1/*3 heterozygous carrier, n = 15; 440.2 ± 146.3 and 14.6 ± 5.1 ng/mL, respectively).
CYP3A4 and CYP3A5 genetic polymorphisms are important factors affecting pharmacokinetic parameters of sirolimus. Our data support the monitoring of blood sirolimus concentrations, especially in CYP3A51 and CYP3A41 G carriers, to ensure accurate dosing in the clinical setting.
西罗莫司是一种用于预防器官移植排斥反应的有前景的免疫抑制药物。然而，西罗莫司药代动力学的个体间差异会导致药物不良反应，影响治疗效果。西罗莫司主要由细胞色素CYP3A4和CYP3A5代谢。本研究旨在阐明CYP3A基因多态性，包括CYP3A41G和CYP3A53多态性对西罗莫司药代动力学的影响。
本研究纳入31名健康中国志愿者。使用Sequenom MassARRAY iPLEX平台测定其基因型，采用液相色谱-串联质谱法（LC-MS/MS）分析不同时间点的血中西罗莫司浓度。使用WinNonlin 5.2版软件计算药代动力学参数。
CYP3A41G和CYP3A53的等位基因频率分别为25.8%和71.0%。在CYP3A41G携带者（n = 13）中，曲线下面积AUC0-144、AUC0-∞和Cmax显著低于CYP3A41/*1纯合子受试者（n = 18）（P < 0.05）。具体而言，*1G/*1G携带者的AUC0-144、AUC0-∞和Cmax分别为315.2±91.5、372.0±108.2和10.2±1.6 ng/mL，*1/1 G1/1 G携带者的分别为440.8±130.6、537.4±167.5和13.7±4.3 ng/mL，而CYP3A41/*1纯合子受试者的分别为540.2±150.6、626.6±166.9和19.8±7.5 ng/mL。在CYP3A5不表达受试者（*3/*3纯合子携带者，n = 15）中，AUC0-144和Cmax分别为549.6±137.9和19.9±7.9 ng/mL，显著高于CYP3A5表达受试者（*1/*1纯合子携带者，n = 2；314.2±129.3和10.3±2.2 ng/mL；*1/*3杂合子携带者，n = 15；440.2±146.3和14.6±5.1 ng/mL）（P < 0.05）。
CYP3A4和CYP3A5基因多态性是影响西罗莫司药代动力学参数的重要因素。我们的数据支持监测血中西罗莫司浓度，尤其是在CYP3A51和CYP3A41 G携带者中，以确保临床用药剂量准确。
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