Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.
Impact of carboxylesterase 1 genetic polymorphism on trandolapril activation in human liver and the pharmacokinetics and pharmacodynamics in healthy volunteers.
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DOI：
10.1111/cts.12989
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Zhu HJ
中科院分区：
文献类型：
--
作者：
Wang X;Her L;Xiao J;Shi J;Wu AH;Bleske BE;Zhu HJ
群多普利是一种血管紧张素转换酶抑制剂前药，需要被肝脏中的羧酸酯酶1（CES 1）激活才能发挥其预期的治疗作用。先前的体外研究表明，CES 1基因变体G143 E（rs71647871）在转染该变体的细胞中消除了CES 1介导的群多普利激活。本研究旨在确定G143 E变体对人类肝脏中群多普利活化的影响以及人类受试者的药代动力学（PK）和药效学（PD）。我们进行了一项体外孵育研究，以评估群多普利在人肝脏中的激活（5例G143 E杂合子和97例非携带者），并在健康志愿者（8例G143 E杂合子和11例非携带者）中进行了群多普利单次给药（1 mg）PK和PD研究。孵育研究显示，G143 E杂合子肝脏中群多普利的平均激活率为未携带该变体肝脏的42%（p = 0.0015）。临床研究表明，相对于非携带者，G143 E携带者的活性代谢物群多普利拉的峰浓度（Cmax）和0 - 72 h曲线下面积（AUC 0 -72 h）分别降低20%和15%，尽管差异无统计学意义。此外，携带者收缩压和舒张压的平均最大降幅分别比非携带者低22%和23%，但差异未达到统计学显著水平。总之，在体外孵育条件下，CES 1 G143 E变体显著损害了群多普利在人肝脏中的活化;然而，该变体对群多普利在健康人类受试者中的PK和PD仅具有适度影响。
Trandolapril, an angiotensin‐converting enzyme inhibitor prodrug, needs to be activated by carboxylesterase 1 (CES1) in the liver to exert its intended therapeutic effect. A previous in vitro study demonstrated that the CES1 genetic variant G143E (rs71647871) abolished CES1‐mediated trandolapril activation in cells transfected with the variant. This study aimed to determine the effect of the G143E variant on trandolapril activation in human livers and the pharmacokinetics (PKs) and pharmacodynamics (PDs) in human subjects. We performed an in vitro incubation study to assess trandolapril activation in human livers (5 G143E heterozygotes and 97 noncarriers) and conducted a single‐dose (1 mg) PK and PD study of trandolapril in healthy volunteers (8 G143E heterozygotes and 11 noncarriers). The incubation study revealed that the mean trandolapril activation rate in G143E heterozygous livers was 42% of those not carrying the variant (p = 0.0015). The clinical study showed that, relative to noncarriers, G143E carriers exhibited 20% and 15% decreases, respectively, in the peak concentration (Cmax) and area under the curve from 0 to 72 h (AUC0–72 h) of the active metabolite trandolaprilat, although the differences were not statistically significant. Additionally, the average maximum reductions of systolic blood pressure and diastolic blood pressure in carriers were ~ 22% and 23% less than in noncarriers, respectively, but the differences did not reach a statistically significant level. In summary, the CES1 G143E variant markedly impaired trandolapril activation in the human liver under the in vitro incubation conditions; however, this variant had only a modest impact on the PK and PD of trandolapril in healthy human subjects.
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