Article

Exploring the role of different drug transport routes in permeability screening

Center of Pharmaceutical Informatics, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-751 23 Uppsala, Sweden.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 02/2005; 48(2):604-13. DOI: 10.1021/jm049711o
Source: PubMed

ABSTRACT The influence of different drug transport routes in intestinal drug permeability screening assays was studied. Three experimental models were compared: the small-intestine-like 2/4/A1 cell model, which has a leaky paracellular pathway, the Caco-2 cell model, which has a tighter paracellular pathway, and artificial hexadecane membranes (HDMs), which exclusively model the passive transcellular pathway. The models were investigated regarding their ability to divide passively and actively transported compounds into two permeability classes and to rank compounds according to human intestinal absorption. In silico permeability models based on two-dimensional (2D) and three-dimensional (3D) molecular descriptors were also developed and validated using external test sets. The cell-based models classified 80% of the acceptably absorbed compounds (FA >/= 30%) correctly, compared to 60% correct classifications using the HDM model. The best compound ranking was obtained with 2/4/A1 (r(s) = 0.74; r(s) = 0.95 after removing actively transported outliers). The in silico model based on 2/4/A1 permeability gave results of similar quality to those obtained when using experimental permeability, and it was also better than the experimental HDM model at compound ranking (r(s) = 0.85 and 0.47, respectively). We conclude that the paracellular transport pathway present in the cell models plays a significant role in models used for intestinal permeability screening and that 2/4/A1 in vitro and in silico models are promising alternatives for drug discovery permeability screening.

2 Followers
 · 
98 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Adult intestinal stem cells (ISC) possess both a long-term proliferation ability and differentiation capability into enterocytes. As a novel in vitro system for the evaluation of drug absorption, we characterized a human small intestinal epithelial cell (HIEC) monolayer that differentiated from adult ISC. Continuous proliferation/differentiation from ISC consistently conferred the capability of maturation of enterocytes to HIEC over 25 passages. The morphologically-matured HIEC monolayer consisted of polarized columnar epithelia with dense microvilli, tight junctions, and desmosomes 8 days after seeding onto culture inserts. Transepithelial electrical resistance across the monolayer was 9-fold lower in HIEC (98.9 ω×cm(2)) than in Caco-2 cells (900 ω×cm(2)), which indicated that the looseness of the tight junctions in the HIEC monolayer was similar to that in the human small intestine (~40 ω×cm(2)). No significant differences were observed in the overall gene expression patterns of the major drug metabolizing enzymes and transporters between the HIEC and Caco-2 cells monolayers. Furthermore, the functions of P-glycoprotein and BCRP in the HIEC monolayer were confirmed by the vectorial transport of marker substrates and their disappearance in the presence of specific inhibitors. The Papp values of paracellularly transported compounds (fluorescein isothiocyanate-dextran 4000, atenolol, and terbutaline) and nucleoside transporter substrates (ribavirin and doxifluridine) in the HIEC monolayer were markedly higher than those of Caco-2 cells, while transcellularly transported drugs (pindolol and midazolam) were equally well permeated. In conclusion, the HIEC monolayer can serve as a novel and superior alternative to the conventional Caco-2 cell monolayer for predicting oral absorption in humans.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; 42(11). DOI:10.1124/dmd.114.059493 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The formal [3+3]cyclization of 3-arylthio-1-silyloxy-1,3-butadienes with 2-aryldiazenyl-3-silyloxy-2-en-1-ones afforded a variety of 2-arylthio-5-aryldiazenylbenzoates.
    Phosphorus Sulfur and Silicon and the Related Elements 01/2014; 189(2). DOI:10.1080/10426507.2013.818999 · 0.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oral absorption depends on many physiological, physiochemical and formulation factors. Two important properties that govern oral absorption are in vitro permeability and solubility, which are commonly used as indicators of human intestinal absorption. Despite this, the nature and exact characteristics of the relationship between these parameters are not well understood. In this study a large dataset of human intestinal absorption was collated along with in vitro permeability, aqueous solubility, melting point, and maximum dose for the same compounds. The dataset allowed a permeability threshold to be established objectively to predict high or low intestinal absorption. Using this permeability threshold, classification decision trees incorporating a solubility-related parameter such as experimental or predicted solubility, or the melting point based absorption potential (MPbAP), along with structural molecular descriptors were developed and validated to predict oral absorption class. The decision trees were able to determine the individual roles of permeability and solubility in oral absorption process. Poorly permeable compounds with high solubility show low intestinal absorption, whereas poorly water soluble compounds with high or low permeability may have high intestinal absorption provided that they have certain molecular characteristics such as a small polar surface or specific topology.
    European Journal of Medicinal Chemistry 12/2014; 90. DOI:10.1016/j.ejmech.2014.12.006 · 3.43 Impact Factor