Growth kinetics of L1210 leukemic cells exposed to different concentration courses of methotrexate in vitro.
At present, pharmacokinetic aspects in existing in vitro assays for cytotoxic drug screening are considered only insufficiently. Using a new microperfusion assay, we integrated the peak plasma concentration (Cmax), the time of peak concentration (tmax), the absorption rate, and the elimination rate following methotrexate (MTX) treatment of L1210 leukemic cells in vitro. The effects of different MTX concentration courses with constant exposure doses (area under the concentration-time curve) were checked by combining the microperfusion assay with the clonogenic assay in agar-containing glass capillaries. We found that the concentration profiles obtained in the ultrafiltration-flat chamber (an essential part of the microperfusion system) can be described by the Bateman function. Thus, the flat chamber might be comprehended as a one-compartmental system with first-order absorption kinetics. We found that the colony-inhibition kinetics of L1210 cells obviously depended on the MTX exposure profile. Continuous cell-growth inhibition was obtained by one concentration profile that offered a compromise between all pharmacokinetic parameters. Our results correlated with the known pharmacodynamic activities of MTX and showed the relevance of different concentration courses to the cytotoxic effect of the drug. We suppose that the growth-inhibition kinetics of unknown, potential anticancer drugs can be also interpreted in similar ways.
Institute of Pharmacy, Free University of Berlin, Germany.
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Gimmel
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Maurer
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D014407:Tumor Cells, Cultured
D008727:Methotrexate