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 elimi- nated 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 quantita- tively assess the principal mechanism for delayed SN-38 elimination. Results The area under the plasma unbound concentration- time curve (AUC u ) 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 un- bound fraction of SN-38 with the plasma CMPF concentra- tion, 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 AUC u 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 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 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 k.fujita@med.showa-u.ac.jp * Yukio Kato ykato@p.kanazawa-u.ac.jp 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 Pharm Res DOI 10.1007/s11095-015-1785-0