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Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

Hepatic uptake of SN-38 via OATP1B1 decreases in ESKD patients through cooperative inhibitory effects of UTs and serum components.

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Abbreviations

ESKD:

End-stage kidney disease

CMPF:

3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid

CYP:

Cytochrome P450

DMSO:

Dimethyl sulfoxide

G418:

Geneticin

HA:

Hippuric acid

HEK:

Human embryonic kidney

HSA:

Human serum albumin

IAA:

Indole-3-acetic acid

IRES:

Internal ribosomal entry site

IS:

3-Indoxyl sulfuric acid

K m :

Michaelis constant

OATP:

Organic anion-transporting polypeptide

UTs:

Uremic toxins

V max :

Maximum velocity

V max/K m :

Intrinsic clearance

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Acknowledgements

We would like to thank patients who provided their blood samples in this study.

Funding

This study was supported financially in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT)-Supported Program for the Strategic Research Foundation at Private Universities, 2012–2016 (S1201008) and by a Grant-in-Aid for Scientific Research (C) (No. 15K08601) from the Japan Society for the Promotion of Science (JSPS) KAKENHI.

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Authors and Affiliations

  1. Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Misasagi Nakauchi-cho, Yamashina-ku, Kyoto, 607-8414, Japan

    Yurie Katsube, Masayuki Tsujimoto, Hiroyoshi Koide, Megumi Ochiai, Ayako Hojyo, Kaori Ogawa, Kengo Kambara, Nao Torii, Daisuke Shima, Tetsuya Minegaki & Kohshi Nishiguchi

  2. Department of Pharmacy Service, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan

    Taku Furukubo & Satoshi Izumi

  3. Department of Medicine, Shirasagi Hospital, 7-11-23 Kumata, Higashisumiyoshi-ku, Osaka, 546-0002, Japan

    Tomoyuki Yamakawa

Authors
  1. Yurie Katsube
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  2. Masayuki Tsujimoto
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  3. Hiroyoshi Koide
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  4. Megumi Ochiai
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  10. Taku Furukubo
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  11. Satoshi Izumi
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  12. Tomoyuki Yamakawa
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  13. Tetsuya Minegaki
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  14. Kohshi Nishiguchi
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Corresponding author

Correspondence to Masayuki Tsujimoto.

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Conflict of interest

Author Tsujimoto has received research grants from the JSPS KAKENHI and grants from Matching Fund Subsidy for Private Universities from the MEXT KAKENHI, during the conduct of the study. The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

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Katsube, Y., Tsujimoto, M., Koide, H. et al. Cooperative inhibitory effects of uremic toxins and other serum components on OATP1B1-mediated transport of SN-38. Cancer Chemother Pharmacol 79, 783–789 (2017). https://doi.org/10.1007/s00280-017-3276-y

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  • DOI: https://doi.org/10.1007/s00280-017-3276-y

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