TAILIEUCHUNG - Báo cáo khoa học: Modulation of P-glycoprotein-mediated multidrug resistance by acceleration of passive drug permeation across the plasma membrane

The drug concentration inside multidrug-resistant cells is the outcome of competition between the active export of drugs by drug efflux pumps, such as P-glycoprotein (Pgp), and the passive permeation of drugs across the plasma membrane. Thus, reversal of multidrug resistance (MDR) can occur either by inhibition of the efflux pumps or by acceleration of the drug per-meation. | ễFEBS Journal Modulation of P-glycoprotein-mediated multidrug resistance by acceleration of passive drug permeation across the plasma membrane Ronit Regev Hagar Katzir Daniella Yeheskely-Hayon and Gera D. Eytan Department of Biology the Technion - Israellnstitute of Technology Haifa Israel Keywords anesthetics modulators multidrug resistance P-glycoprotein propofol Correspondence G. D. Eytan Department of Biology The Technion - Israel Institute of Technology Haifa Israel Fax 972 4 8225153 Tel 972 4 8293406 E-mail eytan@ Website http These authors contributed equally to this work Received 22 July 2007 revised 9 September 2007 accepted 11 October 2007 doi The drug concentration inside multidrug-resistant cells is the outcome of competition between the active export of drugs by drug efflux pumps such as P-glycoprotein Pgp and the passive permeation of drugs across the plasma membrane. Thus reversal of multidrug resistance MDR can occur either by inhibition of the efflux pumps or by acceleration of the drug permeation. Among the hundreds of established modulators of Pgp-mediated MDR there are numerous surface-active agents potentially capable of accelerating drug transbilayer movement. The aim of the present study was to determine whether these agents modulate MDR by interfering with the active efflux of drugs or by allowing for accelerated passive permeation across the plasma membrane. Whereas Pluronic P85 Tween-20 Triton X100 and Cremophor EL modulated MDR by inhibition of Pgp-mediated efflux with no appreciable effect on transbilayer movement of drugs the anesthetics chloroform benzyl alcohol diethyl ether and propofol modulated MDR by accelerating transbilayer movement of drugs with no concomitant inhibition of Pgp-mediated efflux. At higher concentrations than those required for modulation the anesthetics accelerated the passive permeation to such an extent that it was not possible to .

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