Abstract

1. Targeted covalent inhibitors designed to bind covalently to a specific molecular target have recently been a focus of drug development. Among these inhibitors, thiol compounds bind covalently to endogenous thiols in the body through a process involving disulfide bonds.

2. We investigated the predictability of changes in the exposure to captopril, tiopronin, the active form of dalcetrapib and the active metabolite of prasugrel, R-138727, all of which have a sulfhydryl group, in moderate and severe chronic kidney disease (CKD) patients using a constructed PBPK model.

3. The changes in the exposure to captopril, tiopronin and the active form of dalcetrapib under CKD conditions were well predicted. However, the change in exposure to R-138727, which is a secondary metabolite of prasugrel, was overpredicted.

4. Although these thiol compounds covalently bind to endogenous thiols, our study concluded that changes in exposure to these compounds under CKD conditions can probably be predicted, except for compounds with a complicated mechanism whereby the thiol metabolite is generated.

摘要

1. 设计成与特定分子靶标共价结合的靶向共价抑制剂已成为药物开发的重点。在这些抑制剂中，硫醇化合物通过涉及二硫键的过程与体内内源性硫醇共价结合。

2. 在中度和重度慢性肾脏病（CKD）患者中，我们调查了卡托普利，硫普罗宁，dalcetrapib的活性形式和普拉格雷的活性代谢物R-138727（均具有巯基）暴露量变化的可预测性，这些患者使用构建的PBPK模型。

3. 可以很好地预测在CKD条件下卡托普利，硫普罗宁和dalcetrapib活性形式的暴露量变化。但是，R-138727（普拉格雷的次生代谢产物）的暴露量变化被高估了。

4. 尽管这些硫醇化合物与内源性硫醇共价结合，但我们的研究得出的结论是，可以预测在CKD条件下暴露于这些化合物的变化，除了具有复杂机理的化合物会生成硫醇代谢物。