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Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure

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Abstract

Purpose

Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancer patients with severe renal failure (SRF), even though SN-38 is eliminated mainly via the liver. Here, we examined the plasma concentrations of unbound SN-38 in such patients.

Methods

Plasma unbound concentrations were examined by ultrafiltration. Physiologically-based pharmacokinetic (PBPK) models of irinotecan and SN-38 were established to quantitatively assess the principal mechanism for delayed SN-38 elimination.

Results

The area under the plasma unbound concentration-time curve (AUCu) of SN-38 in SRF patients was 4.38-fold higher than that in normal kidney patients. The unbound fraction of SN-38 was also 2.6-fold higher in such patients, partly because SN-38 protein binding was displaced by the uremic toxin 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). This result was supported by correlation of the unbound fraction of SN-38 with the plasma CMPF concentration, which negatively correlated with renal function. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for SRF patients to produce an unbound concentration profile of SN-38 similar to normal kidney patients.

Conclusion

The AUCu of SN-38 in SRF cancer patients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.

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Abbreviations

ABCB1:

ATP-binding cassette, sub-family B, member 1

ABCC2:

ATP-binding cassette, sub-family C, member 2

ABCG2:

ATP-binding cassette, sub-family G, member 2

AUC:

Area under the plasma concentration-time curve

AUCu :

Area under the plasma unbound concentration-time curve

C1,CPT-11 :

Plasma concentration of irinotecan

C1,SN-38 :

Plasma concentration of SN-38

C2,CPT-11 :

Concentration of irinotecan in extracellular space

C2,SN-38 :

Concentration of SN-38 in extracellular space

C3,CPT-11 :

Concentration of irinotecan in hepatocyte

C3,SN-38 :

Concentration of SN-38 in hepatocyte

CES:

Carboxylesterase

CLR,CPT-11 :

Renal clearance of irinotecan

CLR,SN-38 :

Renal clearance of SN-38

CMPF:

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

eGFR:

Estimated glomerular filtration rate

fp,CPT-11 :

Unbound fraction of irinotecan in plasma

fp,SN-38 :

Unbound fraction of SN-38 in plasma

ft,CPT-11 :

Unbound fraction of irinotecan in tissue

ft,SN-38 :

Unbound fraction of SN-38 in tissue

HA:

Hippuric acid

IS:

Indoxyl sulfate

OATPs:

Organic anion transporting polypeptides

PBPK:

Physiologically based pharmacokinetic

PSbile,CPT-11 :

Bile excretion clearance of irinotecan

PSbile,SN-38 :

Bile excretion clearance of SN-38

PSeff,CPT-11 :

Efflux clearance of irinotecan from hepatocyte

PSeff,SN-38 :

Efflux clearance of SN-38 from hepatocyte

PSinf,CPT-11 :

Influx clearance of irinotecan into hepatocyte

PSinf,SN-38 :

Influx clearance of SN-38 into hepatocyte

PSm,CES :

CES-mediated metabolic clearance of irinotecan

PSm,CYP3A :

CYP3A-mediated metabolic clearance of irinotecan

PSm,UGT :

UGT-mediated metabolic clearance of SN-38

PSmBlood,CES :

CES-mediated metabolism of irinotecan in blood

Qh :

Hepatatic blood flow rate

RB,CPT-11 :

Blood-to-plasma partition coefficient of irinotecan

RB,SN-38 :

Blood-to-plasma partition coefficient of SN-38

Rinf :

Infusion rate of irinotecan

SN-38:

7-ethyl-10-hydroxycamptothecin

UGT:

UDP-glucuronosyltransferase

V1,CPT-11,f :

Distribution volume of unbound irinotecan

V1,SN-38,f :

Distribution volume of unbound SN-38

V2 :

Volume of extracellular space in the liver

V3 :

Volume of the liver.

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported in part by a Grant-in-Aid for Scientific Research (C) [23590198 to K.F.] from the Japan Society for the Promotion of Science (JSPS), in part by a Grant-in-Aid for Scientific Research (C) [26460205 to K.F.] and Grant-in-Aid for Young Scientists (B) [26860099 to Y.M.] from the same society, and in part by a Japanese Association of Dialysis Physicians Grant [JADP Grant 2014–1 to K.F.].

We have no conflict of interest to be disclosed.

Author contributions

Y.M., H.O., Y.W., H.S., Yu.S., K.S., K.K., Y.A., Ya.S., Ma. K., and Mu. K. performed the research. K.F., Y.M., H.O., and Y.A. analyzed the data. K.F., Y.M., and Y.K. wrote the manuscript. K.F. and Y.K. designed the research.

Author information

Authors and Affiliations

  1. Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan

    Ken-ichi Fujita & Yasutsuna Sasaki

  2. Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Yusuke Masuo, Hidenori Okumura & Yukio Kato

  3. Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

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

  4. Department of Nephrology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan

    Yusuke Watanabe & Hiromichi Suzuki

  5. Bioorganic Chemistry, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan

    Masanori Kitamura & Munetaka Kunishima

  6. Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo, Tsuzuki-ku, Yokohama, 224-8503, Japan

    Yu Sunakawa

  7. Department of Internal Medicine, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan

    Ken Shimada

  8. Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan

    Yasutsuna Sasaki

Authors
  1. Ken-ichi Fujita
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  2. Yusuke Masuo
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  3. Hidenori Okumura
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  4. Yusuke Watanabe
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  5. Hiromichi Suzuki
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  6. Yu Sunakawa
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  7. Ken Shimada
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  8. Kaori Kawara
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  9. Yuko Akiyama
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  10. Masanori Kitamura
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  11. Munetaka Kunishima
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  12. Yasutsuna Sasaki
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  13. Yukio Kato
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Corresponding authors

Correspondence to Ken-ichi Fujita or Yukio Kato.

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Fujita, Ki., Masuo, Y., Okumura, H. et al. Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure. Pharm Res 33, 269–282 (2016). https://doi.org/10.1007/s11095-015-1785-0

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  • DOI: https://doi.org/10.1007/s11095-015-1785-0

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