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...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 283; no. 1; pp. 391 - 401 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.10.1997
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0022-3565 1521-0103 |