Ken-ichi Fujita1,2, Yusuke Masuo3, Hidenori Okumura3, Yusuke Watanabe4, Hiromichi Suzuki4, Yu Sunakawa5,6, Ken Shimada5,7, Kaori Kawara5, Yuko Akiyama5, Masanori Kitamura8, Munetaka Kunishima8, Yasutsuna Sasaki9,5,10, Yukio Kato11. 1. Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. k.fujita@med.showa-u.ac.jp. 2. Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan. k.fujita@med.showa-u.ac.jp. 3. Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. 4. Department of Nephrology, Saitama Medical University, 38 Morohongou, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan. 5. Department of Medical Oncology, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, 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. Bioorganic Chemistry, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. 9. Institute of Molecular Oncology, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan. 10. Department of Medical Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan. 11. Molecular Pharmacotherapeutics, Faculty of Pharmacy, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan. ykato@p.kanazawa-u.ac.jp.
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 (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. 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.
PURPOSE: Delayed plasma concentration profiles of the active irinotecan metabolite SN-38 were observed in cancerpatients 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. CONCLUSION: The AUC(u) of SN-38 in SRF cancerpatients is much greater than that of normal kidney patients primarily because of the reduced hepatic uptake of SN-38.
Entities:
Keywords:
PBPK model; SN-38; protein binding; severe renal dysfunction; unbound concentration
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