Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, 73.70 avenue Mounier 73, B-1200 Brussels, Belgium
Keywords: antibiotics, efflux, transporters, eukaryotes, influx
Active efflux is now recognized as a key element in drug disposition and activity. Original observations were first limited to a few compounds examined in specific situations, such as anthracyclines in the context of resistance of cancer cells, and tetracyclines in the context of bacterial resistance. However, the combination of systematic surveys involving commonly used drugs and genome sequencing has identified 20 families of drug transporters.1 Many of them are ubiquitous, and are expressed in prokaryotes and archaea as well as in inferior and superior eukaryotes. A companion review2 deals with antibiotic transporters in prokaryotes, where we examine their role and impact on intrinsic antimicrobial activity and resistance. We concentrate here on eukaryotic cells in general, and on animals (including man) in particular, to show how transporters need to be taken into account for a proper understanding as to how antibiotics are handled in vivo.
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Why are antibiotics transported in eukaryotic cells? |
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Occurrence and general properties of antibiotic transporters |
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Influx transporters located at the basolateral membrane will increase the drug concentration within the epithelial cells. If these are bordering the external medium,1315 increased clearance can be obtained provided the drug can diffuse out of these cells. An excellent example is organic anion transporter (OAT)1, which is responsible for the tubular secretion of ß-lactams.16,17 Conversely, an inwards transporter localized at the brush border membrane of epithelial cells can indirectly increase the systemic concentration of its substrates by driving them into these cells, from where they can diffuse into the blood.18,19
Bidirectional transporters have also been found and these can take various roles depending on their localization.2023
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Modulation of the absorption and elimination of antibiotics |
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Barrier effects |
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Drug-inactivating mechanisms and drug transporters may also combine to cause more efficient barrier effects. This concept, which is well known in the case of resistant bacteria (see companion review),2 is now increasingly recognized in mammals, where intestinal and liver transporters cooperate with cytochrome P450-based metabolism to decrease quickly and effectively the amount of active molecules present in the body. Thus, Phase I metabolism adds polar functions to drug molecules, which are further transformed into bioconjugates by Phase II enzymes. The increased polarity of metabolites favours their recognition by efflux pumps,41 as demonstrated with MRP2 for grepafloxacin.29 This has led to the concept of Phase III elimination of drugs.42 Interestingly, the orphan nuclear receptor SXR, which is activated upon exposure to substrates common to cytochromes P450 and MDR, can co-regulate the expression of these two clearance systems.43 The subsequent change in their activity may shed a new light on the specific mechanisms of some drugantibiotic interactions.44 For instance, rifampicin reduces the blood level of several drugs by inducing both cytochrome P450 and MDR expression,45 whereas erythromycin increases that of digoxin, by inhibiting the activity of both proteins.46
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Modulation of cellular accumulation of antibiotics |
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Strategies for the future |
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Inhibition of transporters may also prove useful. An historical example is probenecid, used for a long time as a sparing drug against the renal elimination of ß-lactams and fluoroquinolones. We know today that this effect is mediated, at least in part, by the inhibitory effect probenecid exerts towards OAT and MRP2.69,70 Similar effects on pharmacokinetics or cellular retention have been observed with gemfibrozil, and several other drugs (for example, verapamil and cyclosporin A), which are now known to be modulators of drug transport. The next step should be the design of new chemical entities able to inhibit selectively a given class of transporters, without exerting other pharmacological activities.71,72 This has been partially achieved with preferential inhibitors of MDR or MRP, for instance,7275 some of which are currently being evaluated for their potential use in therapy.76,77 A major unknown in this area is, however, the detrimental effects impairment of transporters may have on the handling of their natural substrates. Thus there is still room for further research aimed at a better understanding of the complex relationships between transporters and the pharmacokinetics, pharmacodynamics and toxicodynamics of antibiotics.
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Acknowledgements |
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Footnotes |
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References |
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