An in vitro pharmacokinetic simulation system that can simulate plasma pharmacokinetics was established to evaluate the @entity137 of two representative antileukemic agents, @entity9864 ( @entity2592 ) and @entity5699 . With this system, the survival rate of the cell line K562 treated with @entity2592 , relative to that of untreated control cells, was 7.1%, as determined by a clonogenic culture technique using a clinically intermediate dose of @entity2592 (1.0 g/m2; 2-h infusion). When the area under the serum concentration-time curve (AUC) was kept constant at infusion times of 2, 4, 8, and 16 h with a regular dose of @entity2592 (100-mg/m2 infusion), the relative cell survival rates were 75, 72, 34, and 14%, respectively. In contrast, with the use of a conventional culture system and a constant concentration-time product (C x T), no time-dependent inhibition effect by @entity2592 was observed, probably due to the @entity2592 inactivation in the cell-containing culture medium. For example, 93% of the @entity2592 in the cell-suspended medium in the conventional culture system was converted to its inactive form, @entity47011 , within 16 h after addition of @entity2592 to the medium. For the simulations of the administration of 50 mg/m2 @entity5699 for 0.5-, 2-, 4-, and 8-h infusions, the relative survival rates [maximal concentrations (Cmaxs)] were 37.4% (0.24 microM), 49.7% (0.089 microM), 72.1% (0.055 microM), and 82.2% (0.032 microM), respectively. With the conventional culture system, the relative survival rates (Cmaxs) following @entity5699 treatment were 7.6% (0.48 microM), 18.6% (0.12 microM), 63.7% (0.06 microM), and 92.0% (0.03 microM) when the drug exposure times were 0.5, 2, 4, and 8 h, respectively, with a constant C x T. When the drug concentration for 90% cell killing by the conventional culture system was plotted against the exposure time on a logarithmic scale, the regression line for @entity5699 had a slope of -0.40, whereas the slope of @entity900 (or @entity900 ), a typical AUC-dependent drug, was -0.98. These results suggested that @entity5699 was Cmax dependent rather than AUC dependent. In the simulation system, this Cmax dependency was apparently reduced, probably because of the smaller difference of Cmaxs in the simulation system compared with the conventional system with the constant AUC. Thus, this simulation system can predict the effects of @entity2592 , @entity5699 , and other antineoplastic agents much more exactly than the conventional culture system in clinical use.

Evaluation of cell-killing effects of @entity9864 and XXXX by a new computer-controlled in vitro pharmacokinetic simulation system.

@entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity5699 :: ('MESH:D003630', 'Chemical') :: ['daunorubicin'] @entity900 :: ('MESH:D002945', 'Chemical') :: ['cisplatin', 'cis-diamminedichloroplatinum'] @entity2592 :: ('MESH:D003561', 'Chemical') :: ['ara-C'] @entity9864 :: ('CHEBI:28680', 'Chemical') :: ['1-beta-D-arabinofuranosylcytosine'] @entity47011 :: ('MESH:D001086', 'Chemical') :: ['1-beta-D-arabinofuranosyluracil']
@entity5699 :: (MESH:D003630,Chemical) :: ['daunorubicin']
