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Review Article |
Faculté de Pharmacie, Université de Montréal, Montreal, Quebec, Canada (L.C., J.T.); and Charles River Laboratories Preclinical Services Montreal Inc., Montreal, Quebec, Canada (L.C., J.A.N.)
Abstract
Abstract I. Introduction II. ATP-Binding Cassette Transporters A. Classification B. Structure and Mechanisms of Action III. ATP-Binding Cassette Transporters and the Disposition of Drugs in Cardiac Tissues A. Evidence for the Presence of ATP-Binding Cassette Transporters in the Heart 1. Use of Different Molecular Biology Techniques. 2. Use of Knockout Mice. B. Cardiotoxicity Related to ATP-Binding Cassette Transporters C. ATP-Binding Cassette Transporters and Drug-Induced Long QT Syndrome IV. Expression of ATP-Binding Cassette Transporters A. Regulation of Expression of ATP-Binding Cassette Transporters 1. Regulation by Drugs. 2. Regulation by Pathological Conditions. B. Polymorphisms V. Summary and Future Perspectives
The passage of drugs across cell membranes dictates their absorption, distribution, metabolism, and excretion. This process is determined by several factors including the molecular weight of the compounds, their shape, degree of ionization, and binding to proteins. Accumulation of xenobiotics into tissues does not depend only on their ability to enter cells, but also on their ability to leave them. For instance, the role of efflux transporters such as ATP-binding cassette (ABC) proteins in the disposition of drugs is now well recognized. Actually, ABC transporters act in synergy with drug-metabolizing enzymes to protect the organism from toxic compounds. The most studied transporter from the ABC transporter superfamily, P-glycoprotein, was found to be overexpressed in tumor cells and associated with an acquired resistance to several anticancer drugs. P-glycoprotein, thought at first to be confined to tumor cells, was subsequently recognized to be expressed in normal tissues such as the liver, kidney, intestine, and heart. Even though information remains rather limited on the functional role of ABC transporters in the myocardium, it is hypothesized that they may modulate efficacy and toxicity of cardioactive agents. This review addresses recent progress on knowledge about the ABC transporters in drug disposition and more precisely their role in drug distribution to the heart.
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