利用内源性生物标志物粪卟啉原 I 对醋酸阿比特龙治疗的前列腺癌患者有机阴离子转运多肽 1B 活性进行特征分析和预测
Characterization and Prediction of Organic Anion Transporting Polypeptide 1B Activity in Prostate Cancer Patients on Abiraterone Acetate Using Endogenous Biomarker Coproporphyrin I.
机构信息
Department of Pharmacy and Pharmaceutical Sciences (Zite.W., K.H.Y.L., E.J.Y.C., E.C.Y.C.) and Department of Surgery, Yong Loo Lin School of Medicine (S.M.T., R.P., E.C.), National University of Singapore, Singapore; Department of Urology (P.C.T., Ziti.W., Q.H.W., W.C.T., A.K., E.C.) and Department of Pharmacy (P.T.W., F.L.), National University Hospital, National University Health System, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore (A.S.C.W.); and National University Cancer Institute, Singapore (P.T.W.).
Department of Pharmacy and Pharmaceutical Sciences (Zite.W., K.H.Y.L., E.J.Y.C., E.C.Y.C.) and Department of Surgery, Yong Loo Lin School of Medicine (S.M.T., R.P., E.C.), National University of Singapore, Singapore; Department of Urology (P.C.T., Ziti.W., Q.H.W., W.C.T., A.K., E.C.) and Department of Pharmacy (P.T.W., F.L.), National University Hospital, National University Health System, Singapore; Department of Haematology-Oncology, National University Cancer Institute, Singapore (A.S.C.W.); and National University Cancer Institute, Singapore (P.T.W.)
出版信息
Drug Metab Dispos. 2024 Oct 16;52(11):1356-1362. doi: 10.1124/dmd.124.001878.
Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We used OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant ( ) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our nine metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3-mediated, but not OATP1B1-mediated, uptake of CP-I in vitro, with an estimated of 3.93 M. Baseline CP-I concentrations were simulated to be 0.81 ± 0.26 ng/ml and determined to be 0.72 ± 0.16 ng/ml among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low. SIGNIFICANCE STATEMENT: The authors used the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multipronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modeling in predicting OATP1B-mediated interaction implicating abiraterone.
有机阴离子转运多肽（OATP）1B1 和 OATP1B3 是重要的肝转运蛋白。我们之前发现 OATP1B3 与阿比特龙的处置密切相关。我们旨在利用已验证的内源性生物标志物粪卟啉 I（CP-I）进一步研究阿比特龙对 OATP1B1 和 OATP1B3 活性的影响。我们使用 OATP1B 转染细胞来表征阿比特龙对 OATP1B 介导的 CP-I 摄取的抑制潜力。抑制常数（Ki）被纳入我们的基于生理学的药代动力学（PBPK）模型中，以模拟接受我们模型指导的 500mg 或临床批准的 1000mg 醋酸阿比特龙（AA）剂量的癌症人群中 CP-I 的系统暴露。模拟数据与我们九名接受 500mgAA 治疗的转移性前列腺癌患者中确定的临床 CP-I 浓度进行了比较。阿比特龙在体外抑制 OATP1B3 介导的，但不抑制 OATP1B1 介导的 CP-I 摄取，估计 Ki 为 3.93M。基线 CP-I 浓度模拟为 0.81±0.26ng/ml，并在转移性前列腺癌患者中确定为 0.72±0.16ng/ml，均高于健康受试者的观察值。PBPK 模拟显示阿比特龙和 CP-I 之间不存在 OATP1B3 介导的相互作用。我们的临床观察证实，CP-I 浓度在接受 500mgAA 治疗后 12 周内仍保持与基线水平相当。使用 CP-I 作为内源性生物标志物，我们在体外鉴定出阿比特龙对 OATP1B3 的抑制作用，但对 OATP1B1 没有抑制作用，这在预测和观察中均被认为无临床意义。我们得出结论，AA 与 OATP1B 底物之间的相互作用风险较低。意义声明：作者使用内源性生物标志物粪卟啉 I（CP-I），并在体外鉴定出阿比特龙是有机阴离子转运多肽（OATP）1B3 的中等抑制剂。随后的基于生理学的药代动力学（PBPK）模拟和临床观察表明，在前列腺癌患者中，阿比特龙和 CP-I 之间不存在 OATP1B 介导的相互作用。这项多方面的研究得出结论，阿比特龙醋酸盐与 OATP1B 底物之间的相互作用风险较低，证明了 PBPK-CP-I 模型在预测涉及阿比特龙的 OATP1B 介导相互作用中的应用。
Zotero 插件