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Drug Metabolism and Disposition Fast Forward
First published on May 28, 2008; DOI: 10.1124/dmd.107.019091

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Received for publication October 9, 2007.
Revised May 17, 2008.
Accepted for publication May 27, 2008.

INTERLEUKIN-2 PRETREATMENT EFFECT ON PACLITAXEL ABSORPTION AND TISSUE DISPOSITION AFTER ORAL AND INTRAVENOUS ADMINISTRATION IN MICE

Hosten Benoit 1*, Abbara Chadi 2, Petit Benoit 3, Dauvin Angelique 3, Bourasset Fanchon 1, Farinotti Robert 1, Gonin Patrick 3, Bonhomme-Faivre Laurence 1

1 UPRES EA 2706, Faculty of Pharmaceutical Sciences, Universite Paris Sud XI Chatenay Malabry, France. 2 Laboratory of pharmacology, Paul-Brousse-Hospital Assistance Publique, Villejuif, France. 3 Animals Department, Institut-Gustave-Roussy Villejuif.

* Address correspondence to: E-mail: hostenb{at}yahoo.fr

Abstract

The aim of the present study was to investigate the effects of recombinant interleukin-2 (rIL-2) treatment on paclitaxel (PLX) pharmacokinetics in the plasma and tissue of Lewis Lung Carcinoma bearing mice (lung tissues and subcutaneous tumours). PLX pharmacokinetics studies were conducted after oral and intravenous administration of 15 mg kg-1 and 4 mg kg-1, respectively, either alone or after three days of rIL-2 pretreatment. The non-compartmental approach was used to determine the mean pharmacokinetic parameters using WinNonLin® software. The influence of rIL-2 pretreatment on physiological P-glycoprotein (P-gp) expression in lung and intestine was investigated by western blot analysis. After oral administration of PLX, AUCs in plasma, lung and subcutaneous tumours were significantly higher (2.98, 2.66 and 3.41-fold, respectively) in the rIL-2 + PLX group as compared to the PLX group. However, no significant effect of rIL-2 pretreatment was observed in plasma or lung following intravenous administration of PLX. PLX AUC in subcutaneous tumours was significantly higher (1.37-fold) with rIL-2 pretreatment as compared to the PLX-alone group after intravenous injection. Pretreatment with rIL-2 appeared to have no effect on PLX plasma terminal half-life when PLX was administered orally or intravenously. However, prolongation of PLX terminal half-life estimated from lung and subcutaneous tumours data had been observed. Increased PLX tissue absorption in the rIL-2 pre-treated group may be explained by a decrease of P-gp expression in the intestines and lung or decreased functionality due to rIL-2. Oral administration allowed the targeted tissues a much higher PLX exposure as compared to intravenous administration.


Key words: ABC transporters, anticancer agents, drug disposition, interleukins, lung cancer, p-glycoprotein, pharmacokinetics




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