Vol. 295, Issue 3, 1276-1283, December 2000

Influence of Antipsychotic, Antiemetic, and Ca²⁺ Channel Blocker Drugs on the Cellular Accumulation of the Anticancer Drug Daunorubicin: P-glycoprotein Modulation

Safaa Ibrahim, James Peggins, Alan Knapton, Thomas Licht and Adorjan Aszalos

Office of Clinical Pharmacology and Biopharmaceutics, Food and Drug Administration, Rockville, Maryland (S.I.); Center for Veterinary Medicine (J.P.) and Division of Applied Pharmacological Research (A.K., A.A.), Food and Drug Administration, Laurel, Maryland; and National Cancer Institute, National Institutes of Health, Bethesda, Maryland (T.L.)

We investigated the effect of antiemetic, antipsychotic, and Ca²⁺ blocker drugs on the function of P-glycoprotein (Pgp) in vitro and compared inhibitory 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, or daunorubicin was measured by flow cytometry in the presence of the drugs. NIH3T3/MDR1 cells were used for reference testing. Results of the flow cytometric studies were supported by cell proliferation and monolayer permeability studies. Thirty-five drugs are included in this study, of which 13 modulate 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 function of Pgp completely if used concomitantly. Based on these in vitro experiments, we conclude that administration of several drugs that modulate the function of Pgp simultaneously may adversely affect the natural function of this efflux pump and may cause drug-induced side effects in patients.