Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38.
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.
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Yurie
Y
Katsube
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan. tsujimt@mb.kyoto-phu.ac.jp.
Masayuki
M
Tsujimoto
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Hiroyoshi
H
Koide
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Megumi
M
Ochiai
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Ayako
A
Hojyo
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Kaori
K
Ogawa
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Kengo
K
Kambara
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Nao
N
Torii
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Daisuke
D
Shima
Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan.
Taku
T
Furukubo
Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan.
Satoshi
S
Izumi
Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan.
Tomoyuki
T
Yamakawa
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Tetsuya
T
Minegaki
Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan.
Kohshi
K
Nishiguchi
D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy / Q000652:urine; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1 / Q000187:drug effects / Q000378:metabolism*; D006435:Renal Dialysis; D012709:Serum Albumin / Q000378:metabolism; D014118:Toxins, Biological / Q000494:pharmacology*; D014511:Uremia / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; D012709:Serum Albumin; D014118:Toxins, Biological; D000077146:Irinotecan; D002166:Camptothecin
End-stage kidney disease; OATP1B1; SN-38; Uremic serum; Uremic toxins