Pazopanib interacts with irinotecan by inhibiting UGT1A1-mediated glucuronidation, but not OATP1B1-mediated hepatic uptake, of an active metabolite SN-38
Pazopanib interacts with irinotecan by inhibiting UGT1A1-mediated glucuronidation, but not OATP1B1-mediated hepatic uptake, of an active metabolite SN-38
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DOI：
10.1007/s00280-019-03784-8
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发表时间：
2019-05-01
影响因子：
3
通讯作者：
Kiuchi, Yuji
中科院分区：
文献类型：
--
作者：
Iwase, Mariko;Fujita, Ken-ichi;Kiuchi, Yuji
目的帕唑帕尼是一种口服活性的多靶点酪氨酸激酶抑制剂。先前的I期研究表明，帕唑帕尼与伊立替康联合给药可增加SN-38（伊立替康的活性代谢产物）的血浆浓度-时间曲线下面积（AUC）。为了阐明药物相互作用的可能机制，我们研究了帕唑帕尼抑制UDP-葡萄糖醛酸基转移酶（UGT）1A 1和有机阴离子转运多肽（OATP）1B 1的潜力，这两种酶分别参与SN-38的解毒和肝摄取。使用OATP 1B 1稳定转染的HEK 293细胞分别评价帕唑帕尼对葡萄糖醛酸化和SN-38肝摄取的抑制作用。进行动力学分析，以估计抑制常数，这是纠正非特异性结合酶源结果在HLM和重组人UGT 1A 1实验中观察到SN-38葡萄糖醛酸化的浓度依赖性抑制：帕唑帕尼通过HLM非竞争性抑制SN-38葡萄糖醛酸化（K-i，K-u = 1.6 +/- 0.05 μ M）和重组人UGT 1A 1（K-i，K-u = 0.69 +/- 0.02 μ M）。使用Ki，K-u值估计的帕唑帕尼诱导的SN-38 AUC增加与接受伊立替康和帕唑帕尼的I期研究患者中观察到的增加相当。这些结果表明，药物-药物相互作用至少部分由UGT 1A 1的抑制介导。相比之下，帕唑帕尼在浓度高达60 μ M时不抑制OATP 1B 1介导的SN-38摄取。结论结果表明，帕唑帕尼抑制UGT 1A 1介导的SN-38葡萄糖醛酸化，但不抑制OATP 1B 1介导的SN-38摄取。
Purpose Pazopanib is an orally active, multi-targeted tyrosine kinase inhibitor. A previous phase I study demonstrated that coadministration of pazopanib with irinotecan increases the area under the plasma concentration-time curve (AUC) for SN-38, an active metabolite of irinotecan. To clarify the possible mechanism underlying that drug-drug interaction, we investigated the potential for pazopanib to inhibit UDP-glucuronosyltransferase (UGT) 1A1 and organic anion-transporting polypeptide (OATP) 1B1, which are involved in detoxification and hepatic uptake of SN-38, respectively.Methods Human liver microsomes (HLMs) and recombinant human UGT1A1, and HEK293 cells stably transfected with OATP1B1 were used to evaluate the inhibitory effects of pazopanib against glucuronidation, and hepatic uptake of SN-38, respectively. Kinetic analysis was performed to estimate inhibition constants, which were corrected for non-specific binding to enzyme sources (K-i,K- u values).Results Concentration-dependent inhibition of SN-38 glucuronidation was observed in the HLMs and recombinant human UGT1A1 experiments: Pazopanib noncompetitively inhibited SN-38 glucuronidation by HLMs (K-i,K- u = 1.6 +/- 0.05 mu M) and recombinant human UGT1A1 (K-i,K- u = 0.69 +/- 0.02 mu M). Pazopanib-induced increases in SN-38 AUC estimated using K-i,K- u values were comparable to those observed in patients of the phase I study who received both irinotecan and pazopanib. Such results suggest that the drug-drug interaction is at least partially mediated by inhibition of UGT1A1. In contrast, pazopanib did not inhibit OATP1B1-mediated SN-38 uptake at concentrations up to 60 mu M.Conclusions Results showed that pazopanib inhibits UGT1A1-mediated SN-38 glucuronidation, but not OATP1B1-mediated SN-38 uptake.