School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China.
Curr Drug Metab. 2022;23(11):912-919. doi: 10.2174/1389200224666221028140652.
Cabozantinib is a multiple receptor tyrosine kinases inhibitor (TKI) approved to treat progressive, metastatic medullary thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Drugdrug interactions (DDIs) for cabozantinib have been identified involving the role of cytochromes P450. Although the previous study reported that cabozantinib showed a slight inhibition of UDP-glucuronosyltransferase (UGT) 1A1 at the highest concentration tested, there are no reports on the potential for UGTs-mediated-DDIs. Hence, the current study aims to address this knowledge gap.
This study aimed to investigate the inhibitory effect of cabozantinib on human UGTs and to quantitatively evaluate the DDI potential via UGT inhibition.
The inhibitory effects of cabozantinib on UGTs were determined by measuring the formation rates for 4- methylumbelliferone (4-MU) glucuronide and trifluoperazine N-glucuronide using recombinant human UGT isoforms in the absence or presence of cabozantinib. Inhibition kinetic studies were conducted to determine the type of inhibition of cabozantinib on UGTs and the corresponding inhibition constant (Ki) value. In vitro-in vivo extrapolation (IVIVE) was further employed to predict the potential risk of DDI in vivo.
Cabozantinib displayed potent inhibition of UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15. Cabozantinib exhibited noncompetitive inhibition towards UGT1A1 and 1A3 and inhibition towards UGT1A7 and 1A9. The Ki,u values (mean ± standard deviation) were calculated to be 2.15±0.11 μM, 0.83±0.05 μM, 0.75±0.04 μM and 0.18 ± 0.10 μM for UGT1A1, 1A3, 1A7 and 1A9, respectively. Co-administration of cabozantinib at the clinically approved dose of 60 mg/day or 140 mg/day may result in approximately a 26% to 60% increase in the systemic exposure of drugs predominantly cleared by UGT1A9, implying a high risk of DDIs.
Cabozantinib has the potential to cause DDIs via the inhibition of UGT1A9; therefore, additional attention should be paid to the safety of the combined use of cabozantinib and drugs metabolized by UGT1A9.
卡博替尼是一种多受体酪氨酸激酶抑制剂（TKI），已被批准用于治疗进展性、转移性甲状腺髓样癌、晚期肾细胞癌和肝细胞癌。已经发现卡博替尼与细胞色素 P450 有关的药物-药物相互作用（DDI）。尽管之前的研究报道卡博替尼在最高测试浓度下对 UDP-葡萄糖醛酸转移酶（UGT）1A1 表现出轻微的抑制作用，但没有关于 UGT 介导的 DDI 潜力的报告。因此，本研究旨在解决这一知识空白。
本研究旨在研究卡博替尼对人 UGT 的抑制作用，并通过 UGT 抑制定量评估潜在的 DDI 可能性。
使用重组人 UGT 同工酶在不存在或存在卡博替尼的情况下，通过测量 4-甲基伞形酮（4-MU）葡萄糖醛酸和三氟拉嗪 N-葡萄糖醛酸的形成速率来确定卡博替尼对 UGT 的抑制作用。进行抑制动力学研究以确定卡博替尼对 UGT 的抑制类型和相应的抑制常数（Ki）值。进一步采用体外-体内外推法（IVIVE）预测体内 DDI 的潜在风险。
卡博替尼对 UGT1A1、1A3、1A4、1A6、1A7、1A8、1A9、1A10、2B7 和 2B15 表现出很强的抑制作用。卡博替尼对 UGT1A1 和 1A3 表现出非竞争性抑制，对 UGT1A7 和 1A9 表现出抑制作用。Ki,u 值（平均值±标准偏差）分别计算为 2.15±0.11 μM、0.83±0.05 μM、0.75±0.04 μM 和 0.18 ± 0.10 μM 用于 UGT1A1、1A3、1A7 和 1A9。当以临床批准的 60 毫克/天或 140 毫克/天的剂量联合使用卡博替尼时，可能会导致主要通过 UGT1A9 清除的药物的全身暴露增加约 26%至 60%，这表明存在发生 DDI 的高风险。
卡博替尼通过抑制 UGT1A9 有引起 DDI 的潜力；因此，应更加注意卡博替尼与 UGT1A9 代谢的药物联合使用的安全性。
