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 monoclonal antibody, was studied in two human colorectal tumor cell lines, HCT-15 and COLO205, whose P-glycoprotein expression is extensive and poor, respectively. In a series of in vitro binding studies, the amount of MRK16 associated with HCT-15 cells at steady state was approximately 40 times greater than that associated with COLO205 cells. In in vivo studies, the disposition of MRK16 was determined in tumor-bearing mice after intravenous administration. The difference in the tumor-to-plasma concentration ratio between the two cell lines was only 2.3-fold at 72 hr after injection. To explain the large difference observed between the in vitro and in vivo results, a series of kinetic simulation studies were performed. By considering the physiological parameters specific for MRK16 (such as permeability-surface area product and the kinetic parameters determined in vitro), the time profiles for the tumor concentration were predicted. The predicted difference in the tumor-to-plasma concentration ratio at 72 hr was calculated to be 2.6-fold, although the permeability-surface area product across the tumor capillary and other physiological parameters were comparable between the two tumor cell lines. The discrepancy between the in vitro and in vivo results was accounted for by the fact that the tumor extracellular fluid concentration at this time point was 13-fold lower in HCT-15 tumors than in COLO205 tumors because of the restricted penetration of MRK16 through the tumor capillaries. This finding suggests that this factor accounts for the in vitro and in vivo difference in the tumor disposition of MRK16.
Mano
Y
Y
Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo, Japan.
Suzuki
H
H
Terasaki
T
T
Iwahashi
T
T
Ono
K
K
Naito
M
M
Tsuruo
T
T
Sugiyama
Y
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal