KINETICS OF CELLULAR PERMEABILITY OF PHENOXAZINE AND ITS DEPENDENCE ON P-GLYCOPROTEIN EXPRESSION

We present here the initial characterization of the mechanism of rever sal of cellular resistance to Vinca alkaloids by phenoxazine (PZ). Cha nges in fluorescence upon cellular accumulation of PZ allowed measurem ent of the membrane transport kinetics in a sensitive KB-3-1 cell line and two multi-drug resistant (MDR) counterparts. The accumulation of PZ is characterized by two uptake routes, with pseudo-first order rate constants of 0.3 s-1 and 0.07 s-1, while efflux of PZ from cells reve aled rate constants of 0.2 s-1. PZ rapidly reaches steady-state concen trations within cells, which may make it more clinically useful than m odulators that accumulate more slowly (e.g. verapamil).