Influence of beta-adrenergic antagonists, H1-receptor blockers, analgesics, diuretics, and quinolone antibiotics on the cellular accumulation of the anticancer drug, daunorubicin: P-glycoprotein modulation

Background: Treatment of patients with several drugs simultaneously may res ult in modulation of the naturally expressed P-glycoprotein (Pgp) at differ ent tissues. With this possibility in mind, we have assessed the ability of different classes of drugs to modulate Pgp function in vitro. Modulation o f the Pgp function was studied at in vitro drug concentrations comparable t o therapeutic blood levels of the drugs. Materials and Methods: Human blood brain barrier endothelial cells and human colon adenocarcinoma cells were transduced or transfected with the multidrug resistance gene (MDR1) to expr ess Pgp. The uptake of fluorescent substrates of Pgp, Rhodamine 123 and dau norubicin, into these cells and NIH3T3/MDR1 and MDCK/MDR1 cells was measure d by flow cytometry and in monolayers in the presence and absence of the di fferent drugs. Results: From the tested six H-1-receptor blockers, seven be ta-adrenergic antagonists, four analgesics, ten diuretics and five quinolon s, five drugs inhibited Pgp at therapeutic blood levels and two at somewhat higher concentrations. Significant synergism for blocking Pgp could be dem onstrated for several drugs. Conclusion: We conclude that administration of several drugs which modulate the function of Pgp to patients may adversely affect the natural function of this efflux pump and malt cause drug-drug i nteractions induced side effects.