Katsube Yurie, Tsujimoto Masayuki, Koide Hiroyoshi, Ochiai Megumi, Hojyo Ayako, Ogawa Kaori, Kambara Kengo, Torii Nao, Shima Daisuke, Furukubo Taku, Izumi Satoshi, Yamakawa Tomoyuki, Minegaki Tetsuya, Nishiguchi Kohshi
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan.
Cancer Chemother Pharmacol. 2017 Apr;79(4):783-789. doi: 10.1007/s00280-017-3276-y. Epub 2017 Mar 17.
Half-life of SN-38, an active metabolite of irinotecan, remarkably increases in patients with end-stage kidney disease (ESKD), even though SN-38 is excreted in bile. Uremic toxins (UTs), which accumulate in the serum of ESKD patients, were reported to inhibit organic anion-transporting polypeptide (OATP) 1B1-mediated uptake of SN-38; however, the relevance of this finding in a clinical setting is unknown. This study focused on cooperative effects of serum components and UTs on OATP1B1-mediated transport of SN-38.
Uptake of SN-38 by OATP1B1 was evaluated using cells stably expressing OATP1B1. Serum was obtained from > 400 ESKD patients undergoing hemodialysis. Deproteinized serum was combined with human serum albumin (HSA) to explore the effects of albumin-bound and unbound serum compounds.
Uptake clearance of SN-38 in OATP1B1 cells decreased by 40% in the presence of uremic serum residue with albumin compared to that in the presence of normal serum residue. Additional UTs (3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, hippuric acid, indole-3-acetic acid, and 3-indoxyl sulfate) combined with normal serum residue in HSA decreased OATP1B1-mediated SN-38 transport by 32.1% compared to that in the presence of normal serum residue. The inhibitory effect of albumin-unbound fraction with UTs and normal serum residue was comparable to that of uremic serum residue, with an uptake decrease of 17.2% compared to that reported in the presence of normal serum residue.
Hepatic uptake of SN-38 via OATP1B1 decreases in ESKD patients through cooperative inhibitory effects of UTs and serum components.
伊立替康的活性代谢产物SN - 38的半衰期在终末期肾病（ESKD）患者中显著延长，尽管SN - 38通过胆汁排泄。据报道，在ESKD患者血清中蓄积的尿毒症毒素（UTs）会抑制有机阴离子转运多肽（OATP）1B1介导的SN - 38摄取；然而，这一发现在临床环境中的相关性尚不清楚。本研究聚焦于血清成分和UTs对OATP1B1介导的SN - 38转运的协同作用。
使用稳定表达OATP1B1的细胞评估OATP1B1对SN - 38的摄取。从400多名接受血液透析的ESKD患者中获取血清。将脱蛋白血清与人血清白蛋白（HSA）结合，以探讨白蛋白结合型和非结合型血清化合物的作用。
与正常血清残余物存在时相比，在存在白蛋白的尿毒症血清残余物时，OATP1B1细胞中SN - 38的摄取清除率降低了40%。与正常血清残余物在HSA中结合的其他UTs（3 - 羧基 - 4 - 甲基 - 5 - 丙基 - 2 - 呋喃丙酸、马尿酸、吲哚 - 3 - 乙酸和3 - 吲哚硫酸酯）与正常血清残余物相比，使OATP1B1介导的SN - 38转运降低了32.1%。UTs和正常血清残余物的白蛋白非结合部分的抑制作用与尿毒症血清残余物相当，与正常血清残余物存在时相比摄取减少了17.2%。
通过UTs和血清成分的协同抑制作用，ESKD患者中经OATP1B1的肝脏对SN - 38的摄取减少。
