共价酪氨酸激酶抑制剂的代谢和药动学

Metabolism and pharmacokinetics of covalent tyrosine kinase inhibitors

共价酪氨酸激酶抑制剂通过与靶蛋白中的半胱氨酸形成共价键,抑制肿瘤细胞的信号通路转导,具有高效能和持续时间长、克服耐药性的优点。本文综述了已经上市的共价酪氨酸激酶抑制剂的代谢和药动学。目前FDA批准上市的共价酪氨酸激酶抑制剂有阿法替尼、来那替尼、达克替尼、奥希替尼、依鲁替尼和阿可替尼。吡咯替尼是由中国自主研发,最近获批上市的抗肿瘤新药。共价酪氨酸激酶抑制剂能够与血浆蛋白,尤其是人血清白蛋白发生共价结合,从而影响这类药物的药动学。

Covalent tyrosine kinase inhibitors(TKIs) can inhibit the signaling pathway of tumor cells by covalent binding with cysteine residues of target proteins, which has the advantages of high potency, extended duration of action and overcoming drug resistance. In this article, we will review the metabolism and pharma‐cokinetics of some covalent TKIs. Currently, the covalent TKIs approved by US food and drug administration(FDA) are afatinib, neratinib, dacomitinib, osimertinib, ibrutinib and acalabrutinib. Pyrotinib have been approved by National Medical Products Administration(NMPA) to reach the market recently. Covalent TKIs can covalently bind with plasma proteins, especially human serum albumin, thus effected the pharmacokinetics of these drugs.