Influence of antipsychotic, antiemetic, and Ca2+ channel blocker drugs on the cellular accumulation of the anticancer drug daunorubicin: P-glycoprotein modulation

We investigated the effect of antiemetic, antipsychotic, and Ca2+ blocker d rugs on the function of P-glycoprotein (Pgp) in vitro and compared inhibito ry concentrations with therapeutic blood levels. Human colon adenocarcinoma (Caco-2) and human blood-brain barrier endothelial cells were transfected or transduced to express Pgp, and the uptake of rhodamine123, calcein AM, o r daunorubicin was measured by flow cytometry in the presence of the drugs. NIH3T3/MDR1 cells were used for reference testing. Results of the flow cyt ometric studies were supported by cell proliferation and monolayer permeabi lity studies. Thirty-five drugs are included in this study, of which 13 mod ulate the function of Pgp at the therapeutic blood concentration and 8 at a concentration 2 to 4 times higher. Two drugs, which block the function of Pgp only partially at therapeutic blood concentrations, blocked the functio n of Pgp completely if used concomitantly. Based on these in vitro experime nts, we conclude that administration of several drugs that modulate the fun ction of Pgp simultaneously may adversely affect the natural function of th is efflux pump and may cause drug-induced side effects in patients.