イリノテカン活性代謝物SN-38の体内動態及びグルクロン酸抱合に及ぼすタクロリムスの影響

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  • 田中 義輝
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University
  • 加藤 美紀
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University
  • 藤岡 美穂
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University
  • 大西 克浩
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University
  • 榊原 有季子
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University
  • 長谷川 高明
    Department of Pharmacy and Pharmacokinetics, Aichi Medical University School of Medicine
  • 灘井 雅行
    Department of Pharmaceutics, Faculty of Pharmacy, Meijo University

書誌事項

タイトル別名
  • Effect of Tacrolimus on the Pharmacokinetics and Glucuronidation of SN-38, an Active Metabolite of Irinotecan
  • イリノテカン カッセイ タイシャブツ SN-38 ノ タイナイ ドウタイ オヨビ グルクロンサン ホウゴウ ニ オヨボス タクロリムス ノ エイキョウ

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説明

  The present study has investigated the effect of tacrolimus on the pharmacokinetics of an active metabolite of irinotecan (CPT-11), 7-ethyl-10-hydroxy-camptothecin (SN-38) and SN-38 glucuronide (SN-38G) in rats. The effect of tacrolimus on SN-38 glucuronidation was also investigated in human and rat liver microsomes. When tacrolimus (0.5 mg/kg) was intravenously injected in rats 15 min before intravenous injection of CPT-11 (5 mg/kg), tacrolimus decreased the plasma concentration of SN-38G. Tacrolimus significantly decreased the area under plasma concentration-time curve (AUC) of SN-38G without change in the mean residence time. On the contrary, significant changes in the pharmacokinetic parameters of SN-38 were not observed. SN-38 glucuronidation in human and rat liver microsomes was inhibited dose-dependently by the presence of tacrolimus and the 50% inhibition concentration (IC50) values of tacrolimus in rat and human liver microsomes were 10.33 μM and 3.58 μM, respectively. When the inhibition type was determined by Lineweaver-Burk and Dixon plots, the inhibition was noncompetitive and the calculated inhibition constant (Ki) values for rat and human liver microsomes were 12.57 μM and 3.88 μM, respectively. These findings suggest that tacrolimus inhibits UGT1A1-mediated SN-38 glucuronidation. Considering the IC50 and Ki values for tacrolimus, it is likely that tacrolimus does not alter the pharmacokinetics of SN-38 and SN-38G at the clinically used dosages, suggesting the possibility that tacrolimus can use safely for cancer patients with irinotecan chemotherapy.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 133 (4), 463-471, 2013

    公益社団法人 日本薬学会

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