| Project/Area Number |
17590131
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Kumamoto University |
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Principal Investigator |
MATSUMOTO Mitsuhiro Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Assosiate Professor, 大学院医学薬学研究部, 助教授 (70253755)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Hideyuki Kumamoto University Hospital, Professor Kumaaoto University, 医学部附属病院, 教授 (40225727)
WATANABE Hiroshi Kumamoto University, School of Pharmacy, Associate frotessor, 薬学部, 講師 (70398220)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | amurubic in / amurubicinol / therapeutic drug monitoring / pharmacokinetics / P-glycoprotein / 細胞膜輸送 / 薬剤耐性 / 個別化 / ファーマコダイナミクス |
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| Research Abstract |
Amrubicin, a synthetic 9-aminoanthracycline agent, was recently approved in Japan for treatment of small-cell lung cancer and non-small-cell lung cancer. Amrubicin is converted enzymatically to the C-13 hydroxy metabolite amrubicinol, which is active and possesses a cytotoxicity 10 to 100 times that of the parent drug. The purpose of this study was to charicterize the pharmacokinetics of amrubicin and its active metabolite amrubicinol. Amrubicin was administered on days 1-3 in 16 patients with advanced lung cancer. The pharmacokinetics analysis of amrubicin and amrubicinol was performed by high-performance liquid chromatography. When 45 mg/m amrubicin was administered in a bolus injection once every 24 hours for 3 consecutive days, the areas under the curves (0 to 72 hours) for amrubicin and amrubicinol were 13,490 and 2585 ng.h/mL, respectively. The apparent total clearance (CL_<app>) of amrubicin was 15.4 L/h. The area-under-the-curve ratio of amrubicinol to amrubicin was 15.1 +/-4.6% (mean +/-SD) at doses ranging from 30 to 45 mg/m. Interindividual variability in the enzymatic conversion of amrubicin to amrubicinol was small. In contrast, a large interindividual variability in the CL_<app> of amrubicin was observed (CV = 49.8%). The areas under the curves of amrubicin and amrubicinol seemed to be associated with the severity of hematologic toxicities. There is a possibility that monitoring of the plasma concentrations of amrubicin and amrubicinol may provide an efficient tool for establishing the optimal dosage of amrubicin in each patient. Furthermore, we found that both amrubicin and amrubicinol are substrates of P-gp. Additionally, the antitumor effects of amrubicin might be affected by P-gp in lung cancer cells. Further studies are warranted to clarify the contribution of P-gp in the antitumor activity and pharmacokinetics of amrubicin.
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