Metabolism and pharmacokinetic study of deuterated osimertinib

IF 1.7 4区医学 Q3 PHARMACOLOGY & PHARMACY

Biopharmaceutics & Drug Disposition Pub Date : 2023-01-17 DOI:10.1002/bdd.2347

Xuyi Zhan, Shaoyin Bao, Xumei Li, Shaojun Zhou, Maha Raja Dahar, Nengming Lin, Xiugui Chen, Chengshan Niu, Kaige Ji, Yusheng Wu, Kui Zeng, Zhihua Tang, Lushan Yu

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Abstract

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.

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氘化奥希替尼的代谢及药代动力学研究

奥西替尼是高选择性的第三代不可逆表皮生长因子受体突变体抑制剂，可用于治疗非小细胞肺癌。作为细胞色素P450酶的底物，在人体内主要被CYP3A酶代谢。在奥西替尼产生的代谢物中，AZ5104和AZ7550是最重要的去甲基化。如今，氘化是一种新的药物设计方法。这种流行的策略被认为可以改善原药的药代动力学特性。因此，本研究比较了奥希替尼及其氘化化合物(奥希替尼-d3)在肝微粒体和人重组细胞色素P450同质酶中的代谢谱以及在大鼠和人体内的药代动力学。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。与奥西替尼相比，大鼠和人血浆中奥西替尼d3的关键代谢物AZ5104的浓度显著降低。这一现象与体外代谢研究结果一致。此外，体内实验结果表明，与大鼠和人体相比，奥希替尼d3具有更高的全身暴露量(AUC)和峰值浓度(Cmax)。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biopharmaceutics & Drug Disposition 医学-药学

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods