Abstract：
Ivacaftor is the first clinically approved monotherapy potentiator to treat CFTR channel dysfunction in people with cystic fibrosis. Ivacaftor (Iva) is a critical component for all current modulator therapies, including highly effective modulator therapies. Clinical studies show that CF patients on ivacaftor-containing therapies present various clinical responses, off-target effects, and adverse reactions, which could be related to metabolites of the compound. In this study, we reported the concentrations of Iva and two of its major metabolites (M1-Iva and M6-Iva) in capillary plasma and estimated M1-Iva and M6-Iva metabolic activity via the metabolite parent ratio in capillary plasma over 12 hours. We also used the ratio of capillary plasma versus human nasal epithelial cell concentrations to evaluate entry into epithelial cells in vivo. M6-Iva was rarely detected by LC-MS/MS in epithelial cells from participants taking ivacaftor, although it was detected in plasma. To further explore this discrepancy, we performed in vitro studies, which showed that M1-Iva, but not M6-Iva, readily crossed 16HBE cell membranes. Our studies also suggest that metabolism of these compounds is unlikely to occur in airway epithelia despite evidence of expression of metabolism enzymes. Overall, our data provide evidence that there are differences between capillary and cellular concentrations of these compounds that may inform future studies of clinical response and off-target effects.
摘要：
Ivacaftor是第一个临床批准的单一疗法增效剂，用于治疗囊性纤维化患者的CFTR通道功能障碍。Ivacaftor（Iva）是当前所有调质疗法的关键组成部分，包括高效的调制疗法。临床研究表明，使用含ivacaftor疗法的CF患者表现出各种临床反应，脱靶效应,和不良反应，这可能与化合物的代谢物有关。在这项研究中,我们报告了Iva及其两种主要代谢物(M1-Iva和M6-Iva)在毛细血管血浆中的浓度,并通过12小时内毛细血管血浆中的代谢物母体比率估计了M1-Iva和M6-Iva的代谢活性.我们还使用毛细血管血浆与人鼻上皮细胞浓度的比率来评估体内进入上皮细胞的情况。通过LC-MS/MS在服用ivacaftor的参与者的上皮细胞中很少检测到M6-Iva，尽管它是在血浆中检测到的。为了进一步探讨这种差异，我们进行了体外研究，这表明M1-Iva，但不是M6-Iva,容易穿过16HBE细胞膜。我们的研究还表明，尽管有代谢酶表达的证据，但这些化合物的代谢不太可能在气道上皮中发生。总的来说,我们的数据提供了这些化合物的毛细血管和细胞浓度之间存在差异的证据,这可能为未来的临床反应和脱靶效应研究提供依据.
