Alteration in the Plasma Concentrations of Endogenous Organic Anion-Transporting Polypeptide 1B Biomarkers in Patients with Non-Small Cell Lung Cancer Treated with Paclitaxel
Alteration in the Plasma Concentrations of Endogenous Organic Anion-Transporting Polypeptide 1B Biomarkers in Patients with Non-Small Cell Lung Cancer Treated with Paclitaxel
复制标题
DOI：
10.1124/dmd.119.089474
复制
发表时间：
2020-05-01
影响因子：
3.9
通讯作者：
Kusuhara, Hiroyuki
中科院分区：
文献类型：
--
作者：
Mori, Daiki;Ishida, Hiroo;Kusuhara, Hiroyuki
在治疗剂量下，紫杉醇被认为会引起OATP 1B介导的药物相互作用;然而，其临床相关性尚未得到证实。本研究旨在使用内源性OATP 1B生物标志物阐明紫杉醇对OATP 1B 1和OATP 1B 3的体内抑制效力。紫杉醇是OATP 1B 1和OATP 1B 3的抑制剂，Ki分别为0.579 +/- 0.107和5.29 +/- 3.87 mM。预孵育增强了其对OATP 1B 1和OATP 1B 3的抑制作用，Ki分别为0.154 +/- 0.031和0.624 +/- 0.183 μ M。招募了10名接受紫杉醇200 mg/m2 3小时输注的非小细胞肺癌患者。10种内源性OATP 1B生物标志物-即粪卟啉I、粪卟啉III、甘氨鹅脱氧胆酸盐-3-硫酸盐、甘氨鹅脱氧胆酸盐-3-葡糖苷酸盐、甘氨脱氧胆酸盐-3-硫酸盐、甘氨脱氧胆酸盐-3-葡糖苷酸盐、石胆酸盐-3-硫酸盐、甘氨石胆酸盐-3-硫酸盐、牛磺石胆酸盐-3-硫酸盐、和鹅去氧胆酸-24-葡萄糖醛酸苷-在非在紫杉醇给药前一天和紫杉醇输注7小时结束后，紫杉醇使内源性生物标志物的血浆浓度-时间曲线下面积（AUC）增加2至4倍，尽管少数患者未显示石胆酸盐-3-硫酸盐、乙醇石胆酸盐-3-硫酸盐和牛磺石胆酸盐-3-硫酸盐的AUC比值增加。用于治疗非小细胞肺癌的紫杉醇治疗剂量（200 mg/m2）将在输注期间和输注结束时引起显著的OATP 1B 1抑制。这是首次证明内源性OATP 1B生物标志物可以作为患者的替代生物标志物。意义声明内源性生物标志物可以解决临床上阐明转运蛋白介导的药物相互作用（DDI）风险的实际和伦理问题。我们可以阐明非小细胞肺癌患者输注（200 mg/（m）2）紫杉醇（一种时间依赖性OATP 1B抑制剂）3小时后内源性OATP 1B生物标志物的血浆浓度显著增加。内源性OATP 1B生物标志物可用于评估患者发生OATP 1B介导DDI的可能性，并有助于适当设计给药方案以避免DDI。
Paclitaxel has been considered to cause OATP1B-mediated drugdrug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with K-i of 0.579 +/- 0.107 and 5.29 +/- 3.87 mM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with K-i of 0.154 +/- 0.031 and 0.624 +/- 0.183 mu M, respectively. Ten patients with non-small cell lung cancer who received 200 mg/m(2) of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers-namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide-were determined in the patients with non-small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2-to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non-small cell lung cancer (200mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients.SIGNIFICANCE STATEMENTEndogenous biomarkers can address practical and ethical issues in elucidating transporter-mediated drug-drug interaction (DDI) risks of anticancer drugs clinically. We could elucidate a significant increment of the plasma concentrations of endogenous OATP1B biomarkers after a 3-hour infusion (200 mg/(m)2) of paclitaxel, a time-dependent inhibitor of OATP1B, in patients with non-small cell lung cancer. The endogenous OATP1B biomarkers are useful to assess the possibility of OATP1Bmediated DDIs in patients and help in appropriately designing a dosing schedule to avoid the DDIs.