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
N1 - Funding Information:
Received; February 29, 2008, Accepted; July 17, 2008 *To whom correspondence should be addressed: Professor Ken-ichi INUI, Ph.D., Department of Pharmacy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan. Tel. ＋81-75-751-3577, Fax. ＋81-75-751-4207, Email: inui＠kuhp.kyoto-u.ac.jp This work was supported in part by a Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by the 21st Century COE Program 'Knowledge Information Infrastructure for Genome Science'.
PY - 2008
Y1 - 2008
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.
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U2 - 10.2133/dmpk.23.469
DO - 10.2133/dmpk.23.469
M3 - Article
C2 - 19122342
AN - SCOPUS:64049116793
SN - 1347-4367
VL - 23
SP - 469
EP - 475
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 6
ER -