Carrier-mediated cellular uptake of pharmaceutical drugs: an exception or the rule?

School of Chemistry and Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 04/2008; 7(3):205-20. DOI: 10.1038/nrd2438
Source: PubMed

ABSTRACT 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.

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous studies indicated that inhibiting efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of TB drugs against Mycobacterium tuberculosis (Mtb) in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited Mtb growth in broth culture (MIC of 19 μg/mL); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline and clofazimine but not with other anti-TB agents. When Mtb was cultured in host macrophage cells, timcodar had about a 10-fold increase (IC50 of 1.9 μg/mL) in the growth inhibition of Mtb and demonstrated synergy with rifampin, moxifloxacin and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid conferring 1.0, and 0.4, log10 reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a long term, chronic infection model of mice treated with a combination of rifampin, isoniazid and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase plasma exposure of bedaquiline. These data suggested that the anti-mycobacterial drug potentiating activity of timcodar is complex, drug dependent and involves both bacterial and host targeted mechanisms. Further study of the improvement of anti-mycobacterial drug and drug candidate potency in combination with timcodar is warranted. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
    Antimicrobial Agents and Chemotherapy 12/2014; · 4.45 Impact Factor
  • [Show abstract] [Hide abstract]
    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.
    Science of The Total Environment 04/2015; 511. · 3.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Aquatic Toxicology 12/2014; 90. · 3.51 Impact Factor


1 Download
Available from