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


CONCLUSIONS
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.
Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. k.fujita@med.showa-u.ac.jp.|Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. k.fujita@med.showa-u.ac.jp.
Ken-ichi
K
Fujita
Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Yusuke
Y
Masuo
Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Hidenori
H
Okumura
Department of Nephrology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.
Yusuke
Y
Watanabe
Department of Nephrology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan.
Hiromichi
H
Suzuki
Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.|Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1 Chigasakichuo, Tsuzuki-ku, Yokohama, 224-8503, Japan.
Yu
Y
Sunakawa
Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.|Department of Internal Medicine, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan.
Ken
K
Shimada
Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
Kaori
K
Kawara
Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.
Yuko
Y
Akiyama
Bioorganic Chemistry, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Masanori
M
Kitamura
Bioorganic Chemistry, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
Munetaka
M
Kunishima
Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.|Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan.|Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan.
Yasutsuna
Y
Sasaki
Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ykato@p.kanazawa-u.ac.jp.
Yukio
Y
Kato
D058186:Acute Kidney Injury / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood* / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000503:physiopathology; D011485:Protein Binding
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
PBPK model; SN-38; protein binding; severe renal dysfunction; unbound concentration