Dabrafenib is a novel small molecule tyrosine kinase inhibitor (TKI) which is used to treat metastatic melanoma. The aim of this research was to survey the effects of dabrafenib on human UDP-glucuronosyltransferases (UGTs) and to evaluate the risk of drug–drug interactions (DDIs). The formation rates for 4-methylumbelliferone (4-MU) glucuronide and trifluoperazine-glucuronide in 12 recombinant human UGT isoforms with or without dabrafenib were measured and HPLC was used to investigate the inhibitory effects of dabrafenib on UGTs. Inhibition kinetic studies were also conducted. In vitro–in vivo extrapolation approaches were further used to predict the risk of DDI potentials of dabrafenib via inhibition of UGTs. Our data indicated that dabrafenib had a broad inhibitory effect on 4-MU glucuronidation by inhibiting the activities of UGTs, especially on UGT1A1, UGT1A7, UGT1A8, and UGT1A9, and dabrafenib could increase the area under the curve of co-administered drugs. Dabrafenib is a strong inhibitor of several UGTs and the co-administration of dabrafenib with drugs primarily metabolized by UGT1A1, 1A7, 1A8 or 1A9 may induce potential DDIs.

中文翻译：

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达拉非尼对人 UDP-葡萄糖醛酸转移酶的抑制作用：对药物相互作用的影响

Dabrafenib 是一种新型小分子酪氨酸激酶抑制剂 (TKI)，用于治疗转移性黑色素瘤。本研究的目的是调查达拉非尼对人 UDP-葡萄糖醛酸基转移酶 (UGT) 的影响并评估药物相互作用 (DDI) 的风险。测量了 4-甲基伞形酮 (4-MU) 葡糖苷酸和三氟拉嗪-葡糖苷酸在 12 种重组人 UGT 同种型中有或没有 dabrafenib 的形成率，并使用 HPLC 研究了 dabrafenib 对 UGT 的抑制作用。还进行了抑制动力学研究。体外-体内外推方法进一步用于通过抑制 UGT 来预测达拉非尼 DDI 潜力的风险。我们的数据表明，达拉非尼通过抑制 UGT 的活性对 4-MU 葡萄糖醛酸化具有广泛的抑制作用，尤其是对 UGT1A1、UGT1A7、UGT1A8 和 UGT1A9 的活性，并且达拉非尼可以增加合用药物的曲线下面积。达拉非尼是几种 UGT 的强抑制剂，达拉非尼与主要由 UGT1A1、1A7、1A8 或 1A9 代谢的药物合用可能会诱发潜在的 DDI。