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 result in modulation of the naturally expressed P-glycoprotein (Pgp) at different tissues. With this possibility in mind, we have assessed the ability of different classes of drugs to modulate Pgp function in vitro. Modulation of the Pgp function was studied at in vitro drug concentrations comparable to therapeutic blood levels of the drugs.


METHODS
Human blood brain barrier endothelial cells and human colon adenocarcinoma cells were transduced or transfected with the multidrug resistance gene (MDR1) to express Pgp. The uptake of fluorescent substrates of Pgp, Rhodamine 123 and daunorubicin, into these cells and NIH3T3/MDR1 and MDCK/MDR1 cells was measured by flow cytometry and in monolayers in the presence and absence of the different drugs.


RESULTS
From the tested six H1-receptor blockers, seven beta-adrenergic antagonists, four analgesics, ten diuretics and five quinolons, five drugs inhibited Pgp at therapeutic blood levels and two at somewhat higher concentrations. Significant synergism for blocking Pgp could be demonstrated for several drugs.


CONCLUSIONS
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 may cause drug-drug interactions induced side effects.
Ibrahim
S
S
Office of Clinical Pharmacology and Biopharmaceutics, Food and Drug Administration, HFD 860, 5600 Fishers Lane, Rockville, MD 20857, USA. ibrahims@cder.fda.gov
Peggins
J
J
Knapton
A
A
Licht
T
T
Aszalos
A
A
D016475:3T3 Cells; D042462:4-Quinolones; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000319:Adrenergic beta-Antagonists; D000700:Analgesics / Q000378:metabolism*; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D018938:Caco-2 Cells; D002460:Cell Line; D002478:Cells, Cultured; D003630:Daunorubicin / Q000378:metabolism*; D004232:Diuretics / Q000378:metabolism*; D004285:Dogs; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression; D006634:Histamine H1 Antagonists / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D042462:4-Quinolones; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D000700:Analgesics; D000890:Anti-Infective Agents; D000903:Antibiotics, Antineoplastic; D004232:Diuretics; D006634:Histamine H1 Antagonists; D003630:Daunorubicin