Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule? Nat Rev Drug Discov 7:205-220

School of Chemistry and Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 04/2008; 7(3):205-20. DOI: 10.1038/nrd2438
Source: PubMed


It is generally thought that many drug molecules are transported across biological membranes via passive diffusion at a rate related to their lipophilicity. However, the types of biophysical forces involved in the interaction of drugs with lipid membranes are no different from those involved in their interaction with proteins, and so arguments based on lipophilicity could also be applied to drug uptake by membrane transporters or carriers. In this article, we discuss the evidence supporting the idea that rather than being an exception, carrier-mediated and active uptake of drugs may be more common than is usually assumed - including a summary of specific cases in which drugs are known to be taken up into cells via defined carriers - and consider the implications for drug discovery and development.

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    • "It is widely believed that bioaccumulation of contaminants occurs through passive diffusion where the hydrophobicity of the compound (logP) largely describes their permeability through membranes (Hamelink and Spacie, 1977; McKim et al., 1985). However, due to their ability to ionise and undergo various transformation processes, there is mounting evidence to support carrier mediated transport of PPCPs through facilitated diffusion and active transport (Dobson and Kell, 2008; Schultz et al., 2010). PPCP occurrence data in aquatic biota is of particular importance as results may highlight highly bioaccumulative compounds that may direct the attention of future risk assessment and management strategies for PPCPs. "
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    ABSTRACT: The development, characterisation and application of a new analytical method for multi-residue PPCP determination in the freshwater amphipod, Gammarus pulex are presented. Analysis was performed using pulverised liquid extraction (PuLE), solid phase extraction (SPE) and liquid chromatography–tandem mass spectrometry (LC–MS/MS). Qualitative method performance offered excellent limits of detection at < 20 ng g− 1 for 18 out of 29 compounds. For quantitative application, linearity and precision were considered acceptable for 10 compounds across the ng-μg g− 1 range (R2 ≥ 0.99; ≤ 20% relative standard deviation respectively). The method was applied to the analysis of G. pulex and river water sourced from six tributaries of the River Thames. Carbamazepine, diazepam, nimesulide, trimethoprim and warfarin were determined in G. pulex samples at low ng g− 1 (dry weight) concentrations across these sites. Temazepam and diclofenac were also detected, but were not quantifiable. Six pharmaceuticals were quantified in surface waters across the eight sites at concentrations ranging from 3 to 344 ng L− 1. The possibility for confirmatory detection and subsequent quantification of pharmaceutical residues in benthic organisms such as G. pulex will enable further understanding on the susceptibility and ecological effects of PPCPs in the aquatic environment.
    Full-text · Article · Apr 2015 · Science of The Total Environment
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    • "We hypothesize that both passive transcellular and carrier-mediated transport of xenobiotics across the gill are likely principle drivers in determining the rate of uptake of waterborne compounds (Mckim and Erickson, 1991). Passive transcellular transport depends on the pH of the solution, acid–base constants (pK a ) and the lipophilicity of the compound, whereas facilitated transport may be via members of the solute carrier (SLC) and ATP-binding casette (ABC) transporter families (Dobson and Kell, 2008). Therefore, to investigate carrier-mediated transport for some of these pharmaceuticals, concentration-equilibrated, pH-dependent, and concentration-dependent assays, as well as membrane channel inhibitor studies were conducted. "
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    ABSTRACT: The gill is the principle site of xenobiotic transfer to and from the aqueous environment. To replace, refine or reduce (3Rs) the large numbers of fish used in in vivo uptake studies an effective in vitro screen is required that mimics the function of the teleost gill. This study uses a rainbow trout (Oncorhynchus mykiss) primary gill cell culture system grown on permeable inserts, which tolerates apical freshwater thus mimicking the intact organ, to assess the uptake and efflux of pharmaceuticals across the gill. Bidirectional transport studies in media of seven pharmaceuticals (propranolol, metoprolol, atenolol, formoterol, terbutaline, ranitidine and imipramine) showed they were transported transcellularly across the epithelium. However, studies conducted in water showed enhanced uptake of propranolol, ranitidine and imipramine. Concentration-equilibrated conditions without a concentration gradient suggested that a proportion of the uptake of propranolol and imipramine is via a carrier-mediated process. Further study using propranolol showed that its transport is pH-dependent and at very low environmentally relevant concentrations (ng L−1), transport deviated from linearity. At higher concentrations, passive uptake dominated. Known inhibitors of drug transport proteins; cimetidine, MK571, cyclosporine A and quinidine inhibited propranolol uptake, whilst amantadine and verapamil were without effect. Together this suggests the involvement of specific members of SLC and ABC drug transporter families in pharmaceutical transport.
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    • "For example, it remains unclear how many chemicals act as substrates of influx transport proteins, and if they do, how much the carrier-mediated uptake contributes to the overall uptake. Dobson and Kell (2008) and Kell et al. (2011) proposed that " essentially all membrane transport of pharmaceuticals is carrier-mediated " . On the other hand, Sugano et al. (2010) and Di et al. (2012) suggested the coexistence of both routes where the contribution of carriermediated transport to the overall uptake of a carrier-mediated compound will depend on the diffusive membrane permeability of the substrate, the kinetic properties of the transport process, the concentration of the transport proteins and the substrate at the membrane, and the electrochemical gradient over the membrane (Sugano et al., 2010). "
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    ABSTRACT: Most toxicokinetic models consider passive diffusion as the only mechanism when modelling the oral uptake of chemicals. However, the overall uptake of nutrients and xenobiotics, such as pharmaceuticals and environmental pollutants, can be increased by influx transport proteins. We incorporated carrier-mediated transport into a one-compartment toxicokinetic model originally developed for passive diffusion only. The predictions were compared with measured oral uptake efficiencies of nutrients and pharmaceuticals, i.e. the fraction of the chemical reaching systemic circulation. Including carrier-mediated uptake improved model predictions for hydrophilic nutrients (RMSE = 10% vs. 56%, Coefficient of Efficiency CoE = 0.5 vs. -9.6) and for pharmaceuticals (RMSE = 21% vs. 28% and CoE = -0.4 vs. -1.1). However, the negative CoE for pharmaceuticals indicates that further improvements are needed. Most important in this respect is a more accurate estimation of vMAX and KM as well as the determination of the amount of expressed and functional transport proteins both in vivo and in vitro.
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