Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.).
Department of Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto, Japan (Y.K., M.T., H.K., T.M., K.N.); Department of Pharmacy, Shiga University of Medical Science Hospital, Shiga, Japan (D.H., Y.I., S.-y.M., T.T.); and College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan (D.H.)
Drug Metab Dispos. 2021 Apr;49(4):289-297. doi: 10.1124/dmd.120.000126. Epub 2021 Jan 14.
Growing evidence suggests that certain glucuronides function as potent inhibitors of CYP2C8. We previously reported the possibility of drug-drug interactions between candesartan cilexetil and paclitaxel. In this study, we evaluated the effects of candesartan 2-glucuronide and candesartan acyl--D-glucuronide on pathways associated with the elimination of paclitaxel, including those involving organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, CYP2C8, and CYP3A4. UDP-glucuronosyltransferase (UGT) 1A10 and UGT2B7 were found to increase candesartan 2-glucuronide and candesartan acyl--D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan 2-glucuronide and candesartan acyl--D-glucuronide by cells stably expressing OATPs is a saturable process with of 5.11 and 12.1 μM for OATP1B1 and 28.8 and 15.7 μM for OATP1B3, respectively; both glucuronides exhibit moderate inhibition of OATP1B1/1B3. Moreover, the hydroxylation of paclitaxel was evaluated using recombinant CYP3A4 and CYP3A5. Results show that candesartan, candesartan 2-glucuronide, and candesartan acyl--D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl--D-glucuronide exhibiting the strongest inhibition (IC is 18.9 µM for candesartan acyl--D-glucuronide, 150 µM for candesartan, and 166 µM for candesartan -glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl--D-glucuronide was not observed. Conversely, the IC values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acyl--D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan and CYP2C8 substrates, including paclitaxel, as a result of the inhibition of CYP2C8 function. SIGNIFICANCE STATEMENT: This study demonstrates that the acyl glucuronidation of candesartan to form candesartan acyl-β-D-glucuronide enhances CYP2C8 inhibition while exerting minimal effects on CYP3A4, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. Thus, candesartan acyl-β-D-glucuronide might represent a potential mediator of drug-drug interactions between candesartan and CYP2C8 substrates, such as paclitaxel, in clinical settings. This work adds to the growing knowledge regarding the inhibitory effects of glucuronides on CYP2C8.
越来越多的证据表明，某些葡萄糖醛酸苷可以作为 CYP2C8 的有效抑制剂。我们之前曾报道坎地沙坦西酯和紫杉醇之间可能存在药物相互作用。在这项研究中，我们评估了坎地沙坦 2-葡萄糖醛酸苷和坎地沙坦酰基-D-葡萄糖醛酸苷对与紫杉醇消除相关的途径的影响，包括涉及有机阴离子转运多肽 (OATP) 1B1、OATP1B3、CYP2C8 和 CYP3A4 的途径。UDP-葡萄糖醛酸基转移酶 (UGT) 1A10 和 UGT2B7 被发现以坎地沙坦浓度依赖的方式增加坎地沙坦 2-葡萄糖醛酸苷和坎地沙坦酰基-D-葡萄糖醛酸苷的形成。此外，稳定表达 OATPs 的细胞对坎地沙坦 2-葡萄糖醛酸苷和坎地沙坦酰基-D-葡萄糖醛酸苷的摄取是一个饱和过程，OATP1B1 的 为 5.11 和 12.1 μM，OATP1B3 的 为 28.8 和 15.7 μM；两种葡萄糖醛酸苷均对 OATP1B1/1B3 表现出中等抑制作用。此外，使用重组 CYP3A4 和 CYP3A5 评估了紫杉醇的羟化作用。结果表明，坎地沙坦、坎地沙坦 2-葡萄糖醛酸苷和坎地沙坦酰基-D-葡萄糖醛酸苷抑制 CYP2C8 介导的紫杉醇代谢，坎地沙坦酰基-D-葡萄糖醛酸苷表现出最强的抑制作用（坎地沙坦酰基-D-葡萄糖醛酸苷的 IC 为 18.9 µM，坎地沙坦的 IC 为 150 µM，坎地沙坦 -葡萄糖醛酸苷的 IC 为 166 µM）。然而，未观察到坎地沙坦酰基-D-葡萄糖醛酸苷对 CYP2C8 的时间依赖性抑制。相反，所有化合物对 CYP3A4 的 IC 值相当。综上所述，这些数据表明，坎地沙坦酰基-D-葡萄糖醛酸苷通过 OATPs 主动转运到肝细胞中，并且由于 CYP2C8 功能的抑制，坎地沙坦和 CYP2C8 底物（包括紫杉醇）的联合用药可能会发生药物相互作用。意义声明：本研究表明，坎地沙坦形成坎地沙坦酰基-β-D-葡萄糖醛酸苷的酰基葡萄糖醛酸化增强了 CYP2C8 的抑制作用，同时对 CYP3A4、有机阴离子转运多肽 (OATP) 1B1 和 OATP1B3 的影响最小。因此，坎地沙坦酰基-β-D-葡萄糖醛酸苷可能是坎地沙坦和 CYP2C8 底物（如紫杉醇）之间药物相互作用的潜在介导物，在临床环境中。这项工作增加了关于葡萄糖醛酸苷对 CYP2C8 的抑制作用的知识。
