Review
KeynoteThe role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox)
Keynote
Section snippets
Introduction—ADME–TOX and ABC transporters in drug discovery
During the process of drug discovery in many cases a new compound or lead molecule is found to act with high affinity and specificity on a desired drug target. However, medical application of this compound will be greatly influenced by its absorption, distribution, metabolism, excretion, and toxicity (ADME–Tox) parameters. Therefore, the fate of the new compound within the body should also be estimated. Moreover, predictive studies should be performed as early as possible in drug development,
Building blocks and the mechanism of action of ABC drug transporters
The evolutionarily conserved family of the ATP binding cassette (ABC) proteins is present in practically all the living organisms from prokaryotes to mammals. The human genome encodes 48 ABC proteins. Sequence alignments revealed that these proteins can be grouped into seven subfamilies, from A to G. According to a general consensus, all functionally active ABC transporters contain a minimum of two ABC units and two TMDs (see Table 1). ABC transporters are large, membrane-bound proteins, built
In vitro assays and models for exploring the role of ABC transporters in ADME–TOX
Characterization of a compound as a transporter substrate or inhibitor bears significant consequences in drug development, the selection of dosing regimens, the anticipation of toxic effects and the potential for drug–drug interactions. The pharmacological relevance of ABC transporters has promoted efforts to establish in vitro systems for testing drug–transporter or drug–drug interactions. Typically, in vitro assays use either cells stably or transiently overexpressing MDR–ABC proteins, or
In vivo assays and model systems
Determining the drug transport capacity of the transporters and extrapolating the results to assess the pharmacological impact of a given drug–transporter interaction has remained a difficult task. Besides technical problems, a major problem is the relevance of in vitro experiments to the in vivo role of MDR–ABC transporters. The in vitro models described above clearly demonstrate the ability of ABC transporters to restrict the cellular uptake and the transcellular passage of drugs. On the
Relevance of MDR–ABC transporters in human pharmacology
The activity of a drug ultimately depends on the ability of the compound to reach its target. MDR–ABC transporters constitute an effective pharmacological barrier by restricting the passage of drugs through membranes. Although several ABC transporters have dedicated functions involving the transport of specific substrates, it is becoming increasingly evident that the complex physiological network of ABC transporters plays a significant role in clinical pharmacology. This role is revealed by the
Improving oral bioavailability and CNS penetration
The hope behind ABC transporter targeted anticancer chemotherapy was that ABC modulation in cancer cells could be achieved without significant consequences in the general pharmacokinetic parameters of the concomitantly administered drugs. Although results of clinical trials have been disappointing, the failures opened an alternative way for the development of the inhibitors, to improve the oral bioavailability and CNS penetration of drugs. There is a clear pharmacological need to overcome
Prospects for drug discovery—save money by spending on transporter assays
As described in detail in the above sections, MDR–ABC transporters have a key role in regulating ADME–Tox. Yet this role is less appreciated in the process of drug discovery and development. One crucial and generally recognized problem in pharmacology is oral availability of a new compound. As of now, simple empirical rules and models, based on molecular descriptors and physicochemical properties are used to predict absorption or permeability properties (oral bioavailability). Lipinski's ‘rule
Acknowledgements
We appreciate the support of the following research grants: OTKA (T48986, PF60435, NK48729, NI68950); ETT; NKTH, NIH (R01TW007250); Marie Curie Grant (046560, 041547). Gergely Szakács is the recipient of a János Bolyai Scholarship and a Special Fellow Award from the Leukemia and Lymphoma Society. Csilla Özvegy-Laczka is a Postdoctoral Fellow (OTKA D45957) and a recipient of the János Bolyai Scholarship.
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