Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats

Akira Yokomasu, Ikuko Yano, Eriko Sato, Satohiro Masuda, Toshiya Katsura, Ken Ichi Inui

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)469-475
Number of pages7
JournalDrug metabolism and pharmacokinetics
Volume23
Issue number6
DOIs
Publication statusPublished - Jan 1 2008

Fingerprint

Pharmacokinetics
Liver
Cyclosporine
Tacrolimus
Intestines
Everolimus
Tandem Mass Spectrometry
Biological Availability
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

Cite this

Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats. / Yokomasu, Akira; Yano, Ikuko; Sato, Eriko; Masuda, Satohiro; Katsura, Toshiya; Inui, Ken Ichi.

In: Drug metabolism and pharmacokinetics, Vol. 23, No. 6, 01.01.2008, p. 469-475.

Research output: Contribution to journalArticle

Yokomasu, Akira ; Yano, Ikuko ; Sato, Eriko ; Masuda, Satohiro ; Katsura, Toshiya ; Inui, Ken Ichi. / Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats. In: Drug metabolism and pharmacokinetics. 2008 ; Vol. 23, No. 6. pp. 469-475.
@article{b4bdd2e88a114452a6c05ad9eebb7ada,
title = "Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats",
abstract = "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.",
author = "Akira Yokomasu and Ikuko Yano and Eriko Sato and Satohiro Masuda and Toshiya Katsura and Inui, {Ken Ichi}",
year = "2008",
month = "1",
day = "1",
doi = "10.2133/dmpk.23.469",
language = "English",
volume = "23",
pages = "469--475",
journal = "Drug Metabolism and Pharmacokinetics",
issn = "1347-4367",
publisher = "Japanese Society for the Study of Xenobiotics",
number = "6",

}

TY - JOUR

T1 - Effect of intestinal and hepatic first-pass extraction on the pharmacokinetics of everolimus in rats

AU - Yokomasu, Akira

AU - Yano, Ikuko

AU - Sato, Eriko

AU - Masuda, Satohiro

AU - Katsura, Toshiya

AU - Inui, Ken Ichi

PY - 2008/1/1

Y1 - 2008/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=64049116793&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=64049116793&partnerID=8YFLogxK

U2 - 10.2133/dmpk.23.469

DO - 10.2133/dmpk.23.469

M3 - Article

C2 - 19122342

AN - SCOPUS:64049116793

VL - 23

SP - 469

EP - 475

JO - Drug Metabolism and Pharmacokinetics

JF - Drug Metabolism and Pharmacokinetics

SN - 1347-4367

IS - 6

ER -