氘代奥希替尼的代谢和药代动力学研究,Biopharmaceutics & Drug Disposition

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氘代奥希替尼的代谢和药代动力学研究
Biopharmaceutics & Drug Disposition ( IF 1.7 ) Pub Date : 2023-01-17 , DOI: 10.1002/bdd.2347
Xuyi Zhan _{1,

2,

3} , Shaoyin Bao _{1,

4} , Xumei Li ₅ , Shaojun Zhou ₁ , Maha Raja Dahar ₁ , Nengming Lin _{2,

6} , Xiugui Chen ₇ , Chengshan Niu ₇ , Kaige Ji ₇ , Yusheng Wu ₇ , Kui Zeng ₁ , Zhihua Tang ₈ , Lushan Yu _{1,

2}

Affiliation

奥希替尼是一种高选择性的第三代表皮生长因子受体突变体不可逆抑制剂，可用于治疗非小细胞肺癌。作为细胞色素P450酶的底物，在人体中主要由CYP3A酶代谢。在奥希替尼、AZ5104 和 AZ7550 产生的代谢物中，去甲基化的代谢物最为重要。如今，氘化是几种药物的新设计方法。这种流行的策略被认为可以改善原始药物的药代动力学特征。因此，在这项研究中，比较了奥希替尼及其氘化化合物 (osimertinib-d3) 在肝微粒体和人重组细胞色素 P450 同工酶中的代谢概况，以及在大鼠和人类中的药代动力学。氘化后，其动力学同位素效应极大地抑制了产生AZ5104的代谢途径。与奥希替尼相比，大鼠和人类中奥希替尼-d3 的关键代谢物 AZ5104 的血浆浓度显着降低。这种现象与体外代谢研究的结果一致。此外，体内结果表明osimertinib-d3具有更高的全身暴露量（AUC）和峰浓度（C_max ) 与大鼠和人体中的 osimertinib 相比。

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Metabolism and pharmacokinetic study of deuterated osimertinib

Osimertinib is a highly selective third-generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non-small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib-d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib-d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib-d3 had higher systemic exposure (AUC) and peak concentration (C_max) compared with the osimertinib in rats and human body.

更新日期：2023-01-17

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