KINETIC-ANALYSIS OF THE DISPOSITION OF MRK16, AN ANTI-P-GLYCOPROTEIN MONOCLONAL-ANTIBODY, IN TUMORS - COMPARISON BETWEEN IN-VITRO AND IN-VIVO DISPOSITION

The kinetics of the disposition of MRK16, an anti-P-glycoprotein monoc lonal antibody, was studied in two human colorectal tumor cell lines, HCT-15 and COLO205, whose P-glycoprotein expression is extensive and p oor, respectively. In a series of in vitro binding studies, the amount of MRK16 associated with HCT-15 cells at steady state was approximate ly 40 times greater than that associated with COLO205 cells. In in viv o studies, the disposition of MRK16 was determined in tumor-bearing mi ce after intravenous administration. The difference in the tumor-to-pl asma concentration ratio between the two cell lines was only 2.3-fold at 72 hr after injection. To explain the large difference observed bet ween the in vitro and in vivo results, a series of kinetic simulation studies were performed. By considering the physiological parameters sp ecific for MRK16 (such as permeability-surface area product and the ki netic parameters determined in vitro), the time profiles for the tumor concentration were predicted. The predicted difference in the tumor-t o-plasma concentration ratio at 72 hr was calculated to be 2.6-fold, a lthough the permeability-surface area product across the tumor capilla ry and other physiological parameters were comparable between the two tumor cell lines. The discrepancy between the in vitro and in vivo res ults was accounted for by the fact that the tumor extracellular fluid concentration at this time point was 13-fold lower in HCT-15 tumors th an in COLO205 tumors because of the restricted penetration of MRK16 th rough the tumor capillaries. This finding suggests that this factor ac counts for the in vitro and in vivo difference in the tumor dispositio n of MRK16.