ATP Binding Cassette (ABC) transporters form a special family of membrane proteins, characterized by homologous ATP-binding, and large, multispanning transmembrane domains. Several members of this family are primary active transporters, which significantly modulate the absorption, metabolism, cellular effectivity and toxicity of pharmacological agents.
This review provides a general overview of the human ABC transporters, their expression, localization and basic mechanism of action. Then we shortly deal with the human ABC transporters as targets of therapeutic interventions in medicine, including cancer drug resistance, lipid and other metabolic disrorders, and even gene therapy applications. We place a special emphasis on the three major groups of ABC transporters involved in cancer multidrug resistance (MDR).
These are the classical P-glycoprotein (MDR1, ABCB1), the multidrug resistance associated proteins (MRPs, in the ABCC subfamily), and the ABCG2 protein, an ABC half-transporter. All these proteins catalyze an ATP-dependent active transport of chemically unrelated compounds, including anticancer drugs. MDR1 (P-glycoprotein) and ABCG2 preferentially extrude large hydrophobic, positively charged molecules, while the members of the MRP family can extrude both hydrophobic uncharged molecules and water-soluble anionic compounds.
Based on the physiological expression and role of these transporters, we provide examples for their role in Absorption-Distribution-Metabolism-Excretion (ADME) and toxicology, and describe several basic assays which can be applied for screening drug interactions with ABC transporters in the course of drug research and development.
The last 15 years marked an expansion in our understanding of how ABC transporters modulate the pharmacokinetic properties of drugs. Assays based on different membrane preparations were one of the first methods developed to study ABC transporters. Later, they turned out to be valuable tools to gain insight into the nature of drug-ABC transporter interactions. Objectives: Membranes prepared from different sources have been used and characterized; based on the biochemical characteristics of the transport process a number of different assay types have been developed.
Methods: This review focuses on the current experiences on how different membrane-based assays can be utilized in pharmaceutical R&D. Sources of membrane preparations, available assay types and correlation studies between different in vitro and in vivo methods are discussed. Results/conclusion: Membrane based assays are valuable tools in drug discovery to characterize drug-ABC transporter interactions.