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Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans

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Abstract

Purpose

Clinical study has previously revealed that plasma concentration of 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of irinotecan, was higher in patients with end-stage renal failure than those with normal kidney function although SN-38 is mainly eliminated in the liver. Here, we focused on inhibition by uremic toxins of hepatic SN-38 uptake and down-regulation of uptake transporter(s) by uremic plasma in humans.

Methods

We evaluated SN-38 uptake and its inhibition by uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulfate (Indox), hippuric acid (HA) and indole acetate (IA), with cryopreserved human hepatocytes and HEK293 cells stably expressing hepatic uptake transporters, organic anion transporting polypeptides (OATPs). We also collected plasma samples from patients with severe renal failure to examine their effects on mRNA level of OATPs in primary cultured human hepatocytes.

Results

SN-38 was taken up by hepatocytes, which showed biphasic saturation patterns. The SN-38 uptake by hepatocytes was significantly inhibited by a uremic toxin mixture including clinically relevant concentrations of CMPF, Indox, HA and IA. Kinetic analyses for OATP-mediated transport revealed that the uptake of SN-38 by OATP1B1 was the highest, followed by OATP1B3. Among the uremic toxins, CMPF exhibited most potent inhibition of OATP1B1-mediated SN-38 uptake and directly inhibited the uptake of SN-38 also in hepatocytes. In addition, gene expression of OATP1B1 and OATP1B3 in hepatocytes was significantly down-regulated by the treatment with the uremic plasma.

Conclusions

OATP1B1-mediated hepatic uptake of SN-38 was inhibited by uremic toxins, and gene expression of OATP1B1 was down-regulated by uremic plasma.

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Abbreviations

ABCB1:

ATP-binding cassette sub-family B, member 1

BCRP:

breast cancer resistance protein

CMPF:

3-carboxy-4-methyl-5-propyl-2-furanpropionate

CLcr :

creatinine clearance

E217βG:

estradiol 17β-D-glucuronide

eGFR:

estimated glomerular filtration rate

HA:

hippuric acid

HPLC:

high-performance liquid chromatography

IA:

indole acetate

Indox:

indoxyl sulfate

MRP2:

multidrug resistance-associated protein 2

OAT:

organic anion transporter

OATP:

organic anion transporting polypeptide

RIF:

rifampicin

RT-PCR:

real-time polymerase chain reaction

SEM:

standard error of mean

SN-38:

7-ethyl-10-hydroxycamptothecin

UGT:

UDP-glucuronosyltransferase

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Acknowledgments and Disclosures

This study was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan [23-A-16], in part by Grant-in-Aid for Scientific Research (B) [24390040] and (C) [23590198] from Japan Society for the Promotion of Science (JSPS), in part by a Grant-in-Aid for “Support Project of Strategic Research Centers in Private Universities” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Saitama Medical University Research Center for Genomic Medicine and in part by Research Grant from National Institute of Biomedical Innovation.

We thank Ms Lica Ishida and Yuko Akiyama for their technical assistance.

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Authors and Affiliations

  1. Department of Medical Oncology, International Medical Center Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

    Ken-ichi Fujita, Yu Sunakawa, Ken Shimada, Kaori Kawara & Yasutsuna Sasaki

  2. Faculty of Pharmacy Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Tomoko Sugiura, Hidenori Okumura, Saki Umeda, Noritaka Nakamichi & Yukio Kato

  3. Department of Nephrology, Saitama Medical University, 38 Morohongo, Moroyama machi, Iruma gun, Saitama, 350-0495, Japan

    Yusuke Watanabe & Hiromichi Suzuki

Authors
  1. Ken-ichi Fujita
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  2. Tomoko Sugiura
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  3. Hidenori Okumura
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  9. Ken Shimada
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  11. Yasutsuna Sasaki
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  12. Yukio Kato
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Correspondence to Yukio Kato.

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Fujita, Ki., Sugiura, T., Okumura, H. et al. Direct Inhibition and Down-regulation by Uremic Plasma Components of Hepatic Uptake Transporter for SN-38, an Active Metabolite of Irinotecan, in Humans. Pharm Res 31, 204–215 (2014). https://doi.org/10.1007/s11095-013-1153-x

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  • DOI: https://doi.org/10.1007/s11095-013-1153-x

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