Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

• Published in: The American journal of tropical medicine and hygiene 2012-07, Vol.87 (1), p.64-69
• Main Authors: OGA, Enoche F, SEKINE, Shuichi, SHITARA, Yoshihisa, HORIE, Toshiharu
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - pharmacology; Antiparasitic agents; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Biological and medical sciences; Caco-2 Cells; Drug Interactions; Humans; Infectious diseases; Medical sciences; Pharmacology. Drug treatments; Rhodamine 123 - metabolism
• ISSN: 0002-9637; 1476-1645
• DOI: 10.4269/ajtmh.2012.11-0817

Antimalarials are widely used in African and Southeast Asian countries, where they are combined with other drugs for the treatment of concurrent ailments. The potential for P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) between antimalarials and P-gp substrates was examined using a Caco-2 cell-based model. Selected antimalarials were initially screened for their interaction with P-gp based on the inhibition of rhodamine-123 (Rho-123) transport in Caco-2 cells. Verapamil (100 μM) and quinidine (1 μM) were used as positive inhibition controls. Lumefantrine, amodiaquin, and artesunate all showed blockade of Rho-123 transport. Subsequently, the inhibitory effect of these antimalarials on the bi-directional passage of digoxin (DIG) was examined. All of the drugs decreased basal-to-apical (B-A) P-gp-mediated DIG transport at concentrations of 100 μM and 1 mM. These concentrations may reflect therapeutic doses for amodiaquin and artesunate. Therefore, clinically relevant DDIs may occur between certain antimalarials and P-gp substrates in general.