Mechanisms of delayed elimination and decreased plasma protein binding of anticancer drugs which are mainly eliminated via the liver in cancer patients with severe renal failure

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460205
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Showa University
• Principal Investigator: Fujita Ken-ichi 昭和大学, 腫瘍分子生物学研究所, 教授 (60281820)
• Co-Investigator(Renkei-kenkyūsha): KATO Yukio 金沢大学, 薬学系, 教授 (30251440) ; SASAKI Yasutsuna 昭和大学, 医学部, 教授 (20235279) ; ANDO Yuichi 名古屋大学, 医学部, 教授 (10360083)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 腎機能障害 / 肝消失型抗がん薬 / イリノテカン / 薬物動態 / SN-38 / 蛋白結合 / PBPKモデル / 投与設計

Outline of Final Research Achievements

The area under the plasma unbound concentration-time curve (AUCu) of SN-38 in patients with severe renal failure was 4.38-fold higher than that in normal kidney patients. This might be a cause of prolonged neutropenia observed in these patients. Decreased hepatic uptake clearance of SN-38 and the higher unbound fraction of SN-38, partly because of the inhibition of SN-38 protein binding by uremic toxins might be causes for the high AUCu of SN-38 in such patients. PBPK modeling indicated substantially reduced influx of SN-38 into hepatocytes and approximately one-third irinotecan dose for patients with severe renal failure to produce an unbound concentration profile of SN-38 similar to normal kidney patients.

Free Research Field

臨床薬理学，薬物動態学，薬理遺伝学