RT Journal Article
SR Electronic
T1 Kinetic Analysis of the Disposition of MRK16, an Anti-P-glycoprotein Monoclonal Antibody, in Tumors: Comparison Between in Vitro and in Vivo Disposition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 391
OP 401
VO 283
IS 1
A1 Yuji Mano
A1 Hiroshi Suzuki
A1 Tetsuya Terasaki
A1 Toshiro Iwahashi
A1 Ken-Ichi Ono
A1 Mikihiko Naito
A1 Takashi Tsuruo
A1 Yuichi Sugiyama
YR 1997
UL http://jpet.aspetjournals.org/content/283/1/391.abstract
AB 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 thein 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 determinedin 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 andin 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 andin vivo difference in the tumor disposition of MRK16. The American Society for Pharmacology and Experimental Therapeutics