Adagrasib (Krazati™)是第二个经FDA批准的针对非小细胞肺癌（NSCLC）携带KRASG12C突变患者的特异性KRASG12C抑制剂。使用基因修改的小鼠模型，研究了药物外排转运蛋白ABCB1和ABCG2以及药物代谢酶CYP3A和羧酸酯酶1（CES1）对口服adagrasib的药动学的影响。在体外实验中，adagrasib在人类ABCB1和小鼠Abcg2中有着强烈和适度的转运作用。在Abcb1a/b-/-和Abcb1a/b;Abcg2-/-小鼠中，脑/血浆比值分别比野生型小鼠增加了33倍和55倍，而在Abcg2-/-小鼠中比值保持不变。同时，双重ABCB1/ABCG2抑制剂elacridar的共同给药完全逆转了ABC转运体的影响，在野生型小鼠中增加了脑部渗透41倍，但未观察到急性中枢神经系统毒性的迹象。因此，肿瘤ABCB1的过表达可能导致adagrasib耐药性。ABCB1和ABCG2转运体对adagrasib的血浆暴露没有影响，而CYP3A和Ces1对其估计的口服可用性产生了强烈的影响。Cyp3a-/-小鼠中，血浆AUC0-8 h显著增加了2.3倍，而在转基因CYP3A4小鼠中显著减少了4.3倍，表明CYP3A介导了大量的代谢。与野生型小鼠相比，Ces1-/-小鼠中，adagrasib血浆暴露显著降低，但组织暴露略有增加，这表明adagrasib在小鼠中与血浆Ces1c结合，并可能通过Ces1代谢。此结合可能会增加小鼠研究的解释复杂性，尤其是考虑到人类缺乏循环CES1酶。我们的结果可能有助于进一步优化adagrasib的临床安全性和疗效，并更深入地了解潜在的药物相互作用风险。版权所有 © 2023 The Authors. 由Elsevier Masson SAS出版。保留所有权利。

Adagrasib (Krazati™) is the second FDA-approved specific KRASG12C inhibitor for non-small cell lung cancer (NSCLC) patients harboring this mutation. The impact of the drug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing enzymes CYP3A and carboxylesterase 1 (CES1) on the pharmacokinetics of oral adagrasib were studied using genetically modified mouse models. Adagrasib was potently transported by human ABCB1 and modestly by mouse Abcg2 in vitro. In Abcb1a/b-/- and Abcb1a/b;Abcg2-/- mice, the brain-to-plasma ratios were enhanced by 33- and 55-fold, respectively, compared to wild-type mice, whereas ratios in Abcg2-/- mice remained unchanged. The influence of ABC transporters was completely reversed by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, increasing the brain penetration in wild-type mice by 41-fold while no signs of acute CNS toxicity were observed. Tumor ABCB1 overexpression may thus confer adagrasib resistance. Whereas the ABC transporters did not affect adagrasib plasma exposure, CYP3A and Ces1 strongly impacted its apparent oral availability. The plasma AUC0-8 h was significantly enhanced by 2.3-fold in Cyp3a-/- compared to wild-type mice, and subsequently 4.3-fold reduced in transgenic CYP3A4 mice, indicating substantial CYP3A-mediated metabolism. Adagrasib plasma exposure was strongly reduced in Ces1-/- compared to wild-type mice, but tissue exposure was slightly increased, suggesting that adagrasib binds to plasma Ces1c in mice and is perhaps metabolized by Ces1. This binding could complicate interpretation of mouse studies, especially since humans lack circulating CES1 enzyme(s). Our results may be useful to further optimize the clinical safety and efficacy of adagrasib, and give more insight into potential drug-drug interactions risks.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.