Potential P-glycoprotein-mediated drug-drug interactions of antimalarial agents in Caco-2 cells

Abstract

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.

Figure 1.

Screening for the inhibition of P-glycoprotein (P-gp)-mediated rhodamine-123 (Rho-123) transport by test antimalarials. Rho-123 (5 μM) was added to the basolateral side of a Caco-2 monolayer, and the basolateral-to-apical (B-A) transport of the tracer dye was measured at 120 min in the presence of test drugs (amodiaquin (ADQ), artemisinin (ASN), artesunate (ART), lumefantrine (LUM), artemether (ATM), chloroquine (CQ), and sulphadoxin (SDX)). Each antimalarial was used at a concentration of 1 mM. Verapamil (VER, 100 μM) and quinidine (QD, 1 μM) were used as the positive inhibition controls. Each column represents the mean ± SEM (N ≥ 3). *Significant difference, P < 0.05 versus control (transport in the absence of drugs).

Figure 2.

Digoxin (DIG) transport kinetics. The bi-directional transport of DIG with or without verapamil (VER, 100 μM) across Caco2 cell monolayers was determined as a function of time. Each data point represents the mean ± SEM of four to seven replicate assays. Solid lines represent basolateral-to-apical (B-A) transport, and dashed lines represent apical-to-basolateral (A-B) transport.

Figure 3.

Digoxin (DIG) and antimalarial drug kinetics. DIG transport across a Caco-2 cell monolayer was examined as a function of time. Apical-to-basolateral (A-B) transport and basolateral-to-apical (B-A) transport of DIG was investigated in the presence or absence of A, lumefantrine (LUM, 100 μM and 1 mM); B, amodiaquin (ADQ, 100 μM and 1 mM); and C, artesunate (ART, 100 μM and 1 mM). Each data point represents the mean ± SEM of at least four determinations. Solid lines represent basolateral-to-apical (B-A) transport, and dashed lines represent apical-to-basolateral (A-B) transport.