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Bevacizumab Modulates P-Glycoprotein Function In vitro and Increases Concentrations of Irinotecan and of its Active Metabolite SN-38 in Plasma of Human Colorectal Carcinoma-Bearing Mice

Mahamadou T, Jean-Meidi A, Chadi A, Marie-Sophie NH, Farah A, Mélanie P, Patrick G and Laurence BF

The overexpression of P-glycoprotein (P-gp) (ABCB1) is associated with multidrug resistance. Since irinotecan and its active metabolite are P-gp substrates, we tested whether bevacizumab, a monoclonal antibody directed toward VEGF (Vascular Endothelial Growth Factor), could modulate P-gp function. The first objective of this study was to evaluate whether bevacizumab could increase intracellular concentration of doxorubicin (P-gp substrate) by interacting with P-gp. The second objective was to document whether bevacizumab could modify irinotecan disposition in mice. Therefore, concentrations of irinotecan and its active metabolite SN-38 were measured by HPLC in plasma of nude mice and in plasma and tumor of mice bearing a human colorectal carcinoma xenograft when irinotecan is given orally (40 mg/kg) on day 3, alone or after a pretreatment with bevacizumab (5 mg/kg IP) on days 1 and 3.

For in vitro studies, two human ovarian carcinoma cells (IGROV1) overexpressing or weakly expressing P-gp were used. Bevacizumab effect on P-gp functionality was evaluated by measuring doxorubicin (P-gp fluorescent substrate) intracellular accumulation. Bevacizumab capacity to increase cytotoxicity was evaluated by MTT test. Exposure to bevacizumab with doxorubicin leads to a significant doxorubicin accumulation and a reversion of doxorubicin resistance in P-gp expressing cell lines. Pharmacokinetic analysis showed a significant increase (1.7 fold) of irinotecan AUC and C_max (2 fold) in plasma after pretreatment with bevacizumab in human colorectal xenograft bearing mice. A non-significant increase in irinotecan tumors AUC (1.3 fold) and C_max (1.3 fold) and SN-38 AUC (1.4 fold) was observed in the bevacizumab treated group. A significant trough concentration of plasma SN-38 (3.9 times higher) in bevacizumab treated nude mice was also observed. Bevacizumab increases a P-gp substrate intracellular accumulation in cell lines suggesting that bevacizumab could influence irinotecan pharmacokinetic partly due to modulation of P-gp fonction.