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Introduction Bevacizumab (BVZ; Avastin®) is an anti-VEGF antibody associated with irinotecan for the treatment of metastatic colorectal cancer. P-glycoprotein (P-gp) has a major role in the multidrug resistance (MDR) phenomenon, responsible for the resistance of cancer cells to chemotherapy. The aim of this study was to assess the influence of BVZ on the functionality of P-gp in vitro, and to document the effect of a BVZ intra peritoneal pretreatment on pharmacokinetics (PK) of irinotecan and SN-38 in plasma after oral administration in Swiss Nude mice. Methods IGR-OV1 cancer cells were incubated with 10 µM doxorubicin during 2 hours. Two concentrations of BVZ were tested: 1 mg/ml and 5 mg/ml. Verapamil, a P-gp inhibitor, was used as the control at 10µM. Functionality of P-gp was assessed by flowcytometry. For the in vivo study, Swiss Nude mice (n=48) were randomly assigned into two groups receiving irinotecan 40 mg/kg orally on day 4 (n=24) or irinotecan 40 mg/kg orally on day 4 with a pretreatment by BVZ 5 mg/kg intraperitoneally on day 1 and day 3 (n=24). The total PK sampling time in each group was 8 points (0.25 hr, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr) and we used 3 mice for each time. Samples were analyzed using high performance liquid chromatography. Results BVZ significantly inhibited P-gp activity in vitro in a dose dependant manner. In vivo, pretreatment with BVZ did not modify the plasma irinotecan and SN-38 AUC. However, SN-38 trough concentration (T+8h) was significantly greater with BVZ pretreatment (p=0.034); the same trend was observed for irinotecan, although the difference was not significant (p=0.084). Pretreatment with BVZ resulted in a SN-38 splitted absorption peak in two parts, whereas the absorption of irinotecan was unaffected. Terminal half-life of irinotecan and SN-38 were not affected by BVZ. Conclusion BVZ did not affect the plasma AUC of irinotecan and SN-38. However, BVZ pretreatment allowed an increase in SN-38 trough concentration: this may be due to an inhibition of the P-gp biliary excretion of SN-38 by BVZ. To complete these results, we are currently studying different administration schedules for BVZ. Table 1 . |
