Increased Plasma Concentrations of Unbound SN-38 ...

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(2) According to the same recovery data, the bile excretion of. SN-38 was 1.4% ... program (version 2.3.1 for Macintosh OS-X; The University of Tokyo Hospital ...

Pharm Res DOI 10.1007/s11095-015-1785-0

RESEARCH PAPER

Increased Plasma Concentrations of Unbound SN-38, the Active Metabolite of Irinotecan, in Cancer Patients with Severe Renal Failure Ken-ichi Fujita 1,3 & Yusuke Masuo 2 & Hidenori Okumura 2 & Yusuke Watanabe 4 & Hiromichi Suzuki 4 & Yu Sunakawa 3,6 & Ken Shimada 3,7 & Kaori Kawara 3 & Yuko Akiyama 3 & Masanori Kitamura 5 & Munetaka Kunishima 5 & Yasutsuna Sasaki 1,3,8 & Yukio Kato 2 Received: 16 April 2015 / Accepted: 26 August 2015 # Springer Science+Business Media New York 2015

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 concentrationtime 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.

KEY WORDS PBPK model . protein binding . severe renal dysfunction . SN-38 . unbound concentration

ABBREVIATIONS ABCB1 ABCC2 ABCG2 AUC

ATP-binding cassette, sub-family B, member 1 ATP-binding cassette, sub-family C, member 2 ATP-binding cassette, sub-family G, member 2 Area under the plasma concentration-time curve

Electronic supplementary material The online version of this article (doi:10.1007/s11095-015-1785-0) contains supplementary material, which is available to authorized users. * Ken-ichi Fujita [email protected] * Yukio Kato [email protected] 1

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

2

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

3

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

4

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

5

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

6

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

7

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

8

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

Fujita et al.

AUCu

C1,CPT-11 C1,SN-38 C2,CPT-11 C2,SN-38

C3,CPT-11 C3,SN-38 CES CLR,CPT-11 CLR,SN-38 CMPF eGFR fp,CPT-11 fp,SN-38 ft,CPT-11 ft,SN-38 HA IS OATPs PBPK PSbile,CPT-11 PSbile,SN-38 PSeff,CPT-11

PSeff,SN-38 PSinf,CPT-11

PSinf,SN-38 PSm,CES

Area under the plasma unbound concentration-time curve Plasma concentration of irinotecan Plasma concentration of SN-38 Concentration of irinotecan in extracellular space Concentration of SN-38 in extracellular space Concentration of irinotecan in hepatocyte Concentration of SN-38 in hepatocyte Carboxylesterase Renal clearance of irinotecan Renal clearance of SN-38 3-Carboxy-4-methyl-5propyl-2-furanpropionate Estimated glomerular filtration rate Unbound fraction of irinotecan in plasma Unbound fraction of SN-38 in plasma Unbound fraction of irinotecan in tissue Unbound fraction of SN-38 in tissue Hippuric acid Indoxyl sulfate Organic anion transporting polypeptides Physiologically based pharmacokinetic Bile excretion clearance of irinotecan Bile excretion clearance of SN-38 Efflux clearance of irinotecan from hepatocyte Efflux clearance of SN-38 from hepatocyte Influx clearance of irinotecan into hepatocyte Influx clearance of SN-38 into hepatocyte CES-mediated metabolic clearance of irinotecan

PSm,CYP3A PSm,UGT PSmBlood,CES Qh RB,CPT-11 RB,SN-38 Rinf SN-38 UGT V1,CPT-11,f V1,SN-38,f V2 V3

CYP3A-mediated metabolic clearance of irinotecan UGT-mediated metabolic clearance of SN-38 CES-mediated metabolism of irinotecan in blood Hepatatic blood flow rate Blood-to-plasma partition coefficient of irinotecan Blood-to-plasma partition coefficient of SN-38 Infusion rate of irinotecan 7-ethyl-10hydroxycamptothecin UDP-glucuronosyltransferase Distribution volume of unbound irinotecan Distribution volume of unbound SN-38 Volume of extracellular space in the liver Volume of the liver.

INTRODUCTION Irinotecan hydrochloride is widely used for cancer chemotherapy. 7-Ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is extensively produced by carboxylesterase (CES) in the liver. SN-38 is subsequently detoxified, predominantly by UDP-glucuronosyltransferase (UGT) 1A1 in the liver, to form SN-38 glucuronide. Transporters expressed in the liver are implicated in various aspects of SN-38 pharmacokinetics. Substantial fractions of SN-38 formed in hepatocytes are transported back into circulation by an unidentified mechanism(s), thereby exerting antitumor activity after delivery to target cells. Organic anion transporting polypeptides (OATPs) 1B1 and OATP1B3, which are localized on sinusoidal membranes, participate in SN-38 uptake into human hepatocytes (1). OATP1B1 has a higher intrinsic uptake clearance of SN-38 into human hepatocytes, followed by OATP1B3 (1). An active transport system is also involved in permeation of SN-38 across canalicular membranes in both humans and rats. ATP-binding cassette, sub-family C, member 2 (ABCC2) and ATP-binding cassette, sub-family G, and member 2 (ABCG2) mediate its biliary excretion (2–4). We have previously reported that the total (bound and unbound) plasma concentration profile of SN-38 was significantly delayed in cancer patients with severe renal failure (creatinine clearance,

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