Disposition of everolimus in mdr1a-/1b-mice and after a pre-treatment of lapatinib in Swiss mice

作者:Chu C*; Abbara C; Noel Hudson M S; Thomas Bourgneuf L; Gonin P; Farinotti R; Bonhomme Faivre L
来源:Biochemical Pharmacology, 2009, 77(10): 1629-1634.
DOI:10.1016/j.bcp.2009.02.013

摘要

The aim of this study was to document the in vivo transport of everolimus (inhibitor of mTOR) by P-glycoprotein (P-gp), and to investigate the influence of lapatinib (inhibitor of P-gp) on everolimus disposition. Pharmacokinetics of everolimus (0.25 mg/kg) has been investigated after oral administration in mdr1a-/1b- mice compared to the wild type. Also, everolimus pharmacokinetics was characterized after oral administration on Swiss mice either alone or after 2 days of pre-treatment of lapatinib (200 mg/kg). The influence of lapatinib pre-treatment on intestinal P-gp expression was investigated by Western blot analysis. The non-compartimental analysis was performed using Winonlin (R) professional version 4.1 software (Pharsight, Mountain View, CA). The areas under the plasma concentration-time Curve (AUC) were compared using Bailer's method. A significant 1.3-fold increase of everolimus AUC observed in mdr1a-/1b- mice suggested that everolimus is transported in vivo by intestinal P-gp in mice. In addition, a 2.6-fold significant increase of everolimus AUC with lapatinib pre-treatment as compared with the everolimus alone group was noticed. The elimination half-life was comparable (t(1/2) 5.3 h vs. t(1/2) = 4 h). A 38.5% significant decrease of P-gp expression was observed in duodenum segment in lapatinib pre-treated group as compared with control group. In conclusion, lapatinib enhanced everolimus absorption by decreasing intestinal P-gp expression. An inhibition of CYP 450 could not be excluded. These results confirm the necessity of a therapeutic monitoring of everolimus combined with an inhibitor of the P-gp and CYP 450 like lapatinib in a future anti-tumor treatment.

  • 出版日期2009-5-15