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Interleukin-2 treatment effect on imatinib pharmacokinetic, P-gp and BCRP expression in mice

Hosten, Benoîta; Abbara, Chadib; Cibert, Marionb; Petit, Benoîtc; Farinotti, Roberta; Gonin, Patrickc; Bonhomme-Faivre, Laurencea b

Anti-Cancer Drugs:
doi: 10.1097/CAD.0b013e3283349913
Preclinical Reports
Abstract

The aim of this study was to investigate the effect that recombinant interleukin-2 (rIL-2) (0.16 MUI/injection) had on the pharmacokinetics of imatinib (IM) in plasma. In this study, IM was given orally to mice at a dose of 150 mg/kg once a day for 11 days (from day 1 to 11) either alone or in combination with intraperitoneal injections of rIL-2 twice a day from day 8 to 11. Pharmacokinetic parameters were determined using WinNonLin software. Areas under the curve were compared using Bailer's method. The repeated administration of the rIL-2+IM combination was shown to have two pharmacokinetic advantages compared with repeated IM doses alone. In addition to the pharmacodynamic interest of this treatment, we found that the combined treatment significantly increased the IM Cmax (P<0.05) and significantly increased the IM trough concentration (C24 h) (P<0.01), which was always above the minimum therapeutic IM concentration (1 μmol/l) in plasma. Those pharmacokinetic modifications may be explained, in part, by a decrease in the P-glycoprotein expression in the three intestinal segments of the mice (duodenum, P<0.01; jejunum, P<0.05; and ileum, P<0.05) and a decrease in BCRP expression in the duodenum segment (P<0.05) due to rIL-2. In another experiment, we found a significant induction of intestinal P-glycoprotein expression in mice that had been given IM orally (150 mg/kg) twice a day for 11 days. It would be interesting to further investigate the IM disposition associated with rIL-2 treatment for clinical applications.

Author Information

aFaculty of Pharmaceutical Sciences, Université Paris Sud XI Châtenay Malabry

bLaboratory of Pharmacology, Paul-Brousse-Hospital Assistance Publique

cAnimals Department, Institut-Gustave-Roussy, Villejuif, France

Correspondence to Dr Benoît Hosten, Laboratory of Pharmacology, Paul-Brousse-Hospital AP-HP, 14 Avenue Paul-Vaillant Couturier, 94800 Villejuif, France

Tel: +33 1 45 59 38 38; fax: +33 1 45 59 37 28;

e-mail: hostenb@yahoo.fr

Received 1 July 2009 Revised form accepted 26 October 2009

© 2010 Lippincott Williams & Wilkins, Inc.