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Abstract
P-glycoprotein (Pgp), a membrane-bound efflux protein, is a member of the ATP Binding Cassette (ABC) superfamily, and it plays a pivotal role in the elimination of a vast majority of drugs, including cardiovascular disease (CVD) drugs, across the plasma membrane. The cardiac glycosides (CGs) are a class of CVD drugs that exhibit interactions with Pgp, and due to their increased concentration in patient plasma, ultimately resulting in arrhythmia and death. The CGs have a narrow therapeutic index, and combined with their binding to Pgp, often results in decreased drug bioavailability, adverse drug reactions (ADRs), and toxicity. Therefore, understanding the structural and molecular mechanisms of interactions between CG and Pgp is necessary to inhibit Pgp-mediated transport. In this study, we demonstrated a comparative analysis of four CGs: digoxin, digitoxin, digoxigenin, and digitoxigenin, and their interactions with Pgp to further understand the Pgp-mediated transport of CGs. The binding studies, coupled with alterations in Pgp conformation analysis and determination of the effect of each drug on the ATPase activity of Pgp, along with previous Pgp-mediated CG transport studies, were combined to propose a model for CG-induced Pgp-mediated ATP hydrolysis and transport.