Inostamycin, an inhibitor of P-glycoprotein function, interacts specifically with phosphatidylethanolamine.

The mechanism of inostamycin action was further studied. When multidrug-resistant KB-C4 cells were preincubated with inostamycin for 30 min, the accumulation of [3H]vinblastine was increased for as long as 48 h thereafter. Inostamycin inhibited azidopine binding to P-glycoprotein, even after KB plasma membranes had been preincubated with inostamycin and washed. Carbon 14-labeled inostamycin bound to KB plasma membranes irreversibly, but the binding capacity did not parallel the amount of P-glycoprotein in three KB cell lines. Inostamycin was found to interact specifically with purified phosphatidylethanolamine. These results suggest that inostamycin can inhibit P-glycoprotein irreversibly by binding to plasma membranes irreversibly through phosphatidylethanolamine.