Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918

The acridone carboxamide derivative GG918 (N-{4-[2-(1,2,3,4-tetrahydro-6,7- dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10- dihydro-5-methoxy-9-oxo-4-a cridine carboxamide) is a potent inhibitor of MDR1 P-glycoprotein-mediated multidrug resistance. Direct measurements of ATP-dependent MDR1 P-glycoprot ein-mediated transport in plasma membrane vesicles from human and rat hepat ocyte canalicular membranes indicated 50% inhibition at GG918 concentration s between 8 nM and 80 nM using N-pentyl-[H-3]quinidinium, [C-14]doxorubicin and [H-3]daunorubicin as substrates. The inhibition constant K-i for GG918 was 35 nM in rat hepatocyte canalicular membrane vesicles with [H-3]daunor ubicin as the substrate. Photoaffinity labelling of canalicular and recombi nant rat Mdr1b P-glycoprotein by [H-3]azidopine was suppressed by 10 mu M a nd 40 mu M GG918. The high selectivity of GG918-induced inhibition was demo nstrated in canalicular membrane vesicles and by analysis of the hepatobili ary elimination in rats using [H-3]daunorubicin, [H-3]taurocholate and [H-3 ]cysteinyl leukotrienes as substrates for three distinct ATP-dependent expo rt pumps. Almost complete inhibition of [H-3]daunorubicin transport was obs erved at GG918 concentrations that did not affect the other hepatocyte cana licular export pumps. The high potency and selectivity of GG918 for the inh ibition of human MDR1 and rat Mdr1b P-glycoprotein may serve to interfere w ith this type of multidrug resistance and provides a tool for studies on th e function of these ATP-dependent transport proteins.