Kinetics of cellular permeability of phenoxazine and its dependence on P-glycoprotein expression

We present here the initial characterization of the mechanism of reversal of cellular resistance to Vinca alkaloids by phenoxazine (PZ). Changes in fluorescence upon cellular accumulation of PZ allowed measurement 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 revealed rate constants of 0.2 s-1. PZ rapidly reaches steady-state concentrations within cells, which may make it more clinically useful than modulators that accumulate more slowly (e.g. verapamil).