The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart.
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.
Couture
Lucie
L
Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal, Quebec, Canada, H3C 3J7.
Nash
John A
JA
Turgeon
Jacques
J
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000633:toxicity; D001692:Biological Transport; D002121:Calcium Channel Blockers / Q000494:pharmacology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D006321:Heart / Q000187:drug effects*; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014700:Verapamil