Effect of Intestinal and Hepatic First-pass Extraction on the Pharmacokinetics of Everolimus in Rats

• YOKOMASU Akira

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

• YANO Ikuko

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

• SATO Eriko

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

• MASUDA Satohiro

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

• KATSURA Toshiya

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

• INUI Ken-ichi

  Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University

抄録

  The aim of this study was to quantitatively evaluate the effects of intestinal and hepatic extraction on the pharmacokinetics of everolimus in rats. Everolimus was administered intravenously, intraportally or intraintestinally in order to separately evaluate the intestinal and hepatic first-pass extraction. Cyclosporine or tacrolimus was administered into rat intestines, and after 10 min everolimus pharmacokinetics were evaluated. The blood concentrations of everolimus were measured by the high-performance liquid chromatography with tandem mass spectrometry. Total body clearance of everolimus was constant in the dosage from 0.2 to 1.0 mg/kg. The bioavailability after intraportal and intraintestinal administration were 48.0% and 21.2%, respectively. Concomitantly administered cyclosporine (5 mg/kg) , but not tacrolimus (1 mg/kg), significantly decreased the total body clearance of everolimus compared with the control, and also increased the bioavailabilty of everolimus after intraintestinal administration 1.75-fold. Cyclosporine significantly increased the area under the blood concentration-time curve of everolimus after the intraintestinal constant infusion 3-fold, and increased that after the intraportal constant infusion only 1.35-fold. In conclusion, the intestine as well as liver contributes to the first-pass extraction for everolimus in rats. Intestinally administered cyclosporine inhibited the intestinal extraction of everolimus more than its hepatic extraction.<br>

収録刊行物

• Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ

  Ｄｒｕｇ　Ｍｅｔａｂｏｌｉｓｍ　ａｎｄ　Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 23 (6), 469-475, 2008

  日本薬物動態学会

キーワード

• everolimus
• first-pass effect
• pharmacokinetics
• cyclosporine
• tacrolimus
• interaction

詳細情報

• CRID: 1390282680156402944
• NII論文ID: 10025722222
• NII書誌ID: AA1162652X
• DOI: 10.2133/dmpk.23.469
• ISSN: 18800920
• ISSN: 13474367
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715302238?httpAccept=text/xml
• Web Site: http://api.elsevier.com/content/article/PII:S1347436715302238?httpAccept=text/plain
• Web Site: https://search.jamas.or.jp/link/ui/2009145226
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可