Current methodologies used for evaluation of intestinal permeability and absorption.

This review article will focus on the various techniques that are currently employed by drug discovery scientists in evaluating permeability/absorption of drug candidates during the drug candidate selection process. Various preclinical methodologies are available; each having advantages and disadvantages, but it is the judicious use of these techniques that can help identify drug candidates that will be well absorbed in humans. It is well recognized that the human intestinal permeability cannot be accurately predicted based on a single methodology (in vitro: tissue/cell culture, in situ, or in vivo).

[1]  B. Brodie,et al.  Absorption of drugs from the rat small intestine. , 1958, The Journal of pharmacology and experimental therapeutics.

[2]  P. Artursson,et al.  A conditionally immortalized epithelial cell line for studies of intestinal drug transport. , 1999, The Journal of pharmacology and experimental therapeutics.

[3]  J. Schullek,et al.  A high-density screening format for encoded combinatorial libraries: assay miniaturization and its application to enzymatic reactions. , 1997, Analytical biochemistry.

[4]  E. Krause,et al.  Noncovalent immobilized artificial membrane chromatography, an improved method for describing peptide-lipid bilayer interactions. , 1999, Journal of chromatography. A.

[5]  W. Higuchi,et al.  Quantitative mechanistic studies in simultaneous fluid flow and intestinal absorption using steroids as model solutes , 1980 .

[6]  K. Isselbacher,et al.  Glucose transport in isolated brush border membrane from rat small intestine. , 1973, The Journal of biological chemistry.

[7]  P. Toner,et al.  Morphology of the Intestinal Mucosa , 1984 .

[8]  W. Rubas,et al.  Flux measurements across Caco-2 monolayers may predict transport in human large intestinal tissue. , 1996, Journal of pharmaceutical sciences.

[9]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[10]  K. Hillgren,et al.  In vitro systems for studying intestinal drug absorption , 1995, Medicinal research reviews.

[11]  K Gubernator,et al.  Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. , 1998, Journal of medicinal chemistry.

[12]  Thomas J. Raub,et al.  Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. , 1989, Gastroenterology.

[13]  T. H. Wilson,et al.  The use of sacs of everted small intestine for the study of the transference of substances from the mucosal to the serosal surface , 1954, The Journal of physiology.

[14]  K. Luthman,et al.  Caco-2 monolayers in experimental and theoretical predictions of drug transport , 1996 .

[15]  G. Amidon,et al.  Absorption potential: estimating the fraction absorbed for orally administered compounds. , 1985, Journal of pharmaceutical sciences.

[16]  John G. Houston,et al.  A 384-HTS for Human Factor VIIa: Comparison With 96- and 864-Well Formats , 1997 .

[17]  P. Artursson Cell cultures as models for drug absorption across the intestinal mucosa. , 1991, Critical reviews in therapeutic drug carrier systems.

[18]  S. Krämer,et al.  Absorption prediction from physicochemical parameters. , 1999, Pharmaceutical science & technology today.

[19]  P. Sinko,et al.  Oral absorption of anti-AIDS nucleoside analogues. 1. Intestinal transport of didanosine in rat and rabbit preparations. , 1995, Journal of pharmaceutical sciences.

[20]  O. H. Chan,et al.  Use of immobilized artificial membrane chromatography for drug transport applications. , 1998, Journal of pharmaceutical sciences.

[21]  Alfred J. Kolb,et al.  Beyond the 96-Well Microplate: Instruments and Assay Methods for the 384-Well Format , 1997 .

[22]  H H USSING,et al.  Active transport of sodium as the source of electric current in the short-circuited isolated frog skin. , 1951, Acta physiologica Scandinavica.

[23]  A. Tsuji,et al.  GI absorption of beta-lactam antibiotics II: deviation from pH--partition hypothesis in penicillin absorption through in situ and in vitro lipoidal barriers. , 1978, Journal of pharmaceutical sciences.

[24]  P. Artursson,et al.  Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells. , 1991, Biochemical and biophysical research communications.

[25]  H Lennernäs,et al.  Human intestinal permeability. , 1998, Journal of pharmaceutical sciences.

[26]  C. Pidgeon,et al.  Immobilized Artificial Membranes — screens for drug membrane interactions , 1997 .

[27]  E. L. Noach,et al.  The influence of diphenylhydantoin on intestinal glucose absorption in the rat. , 1974, European journal of pharmacology.

[28]  G. Amidon,et al.  Predicted absorption rates with simultaneous bulk fluid flow in the intestinal tract. , 1981, Journal of theoretical biology.

[29]  Elizabeth M. Topp,et al.  Transport processes in pharmaceutical systems , 1999 .

[30]  R. Kimura,et al.  The effect of surgical bowel manipulation and anesthesia on intestinal glucose absorption in rats. , 1995, The Journal of clinical investigation.

[31]  L. Johnson,et al.  Physiology of the gastrointestinal tract , 2012 .

[32]  A. Daugherty,et al.  Transcellular uptake mechanisms of the intestinal epithelial barrier Part one. , 1999, Pharmaceutical science & technology today.

[33]  Thomas D.Y. Chung,et al.  Assay Miniaturization for Ultra-High Throughput Screening of Combinatorial and Discrete Compound Libraries: A 9600-Well (0.2 Microliter) Assay System , 1998 .

[34]  J. Bridges,et al.  A re-evaluation of the importance of partition coefficients in the gastrointestinal absorption of anutrients. , 1974, The Journal of pharmacology and experimental therapeutics.

[35]  J. Tolan,et al.  MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. , 1999, Journal of pharmaceutical sciences.

[36]  Q. Yang,et al.  Immobilized-liposome chromatographic analysis of drug partitioning into lipid bilayers. , 1995, Journal of chromatography. A.

[37]  D. E. Clark Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. , 1999, Journal of pharmaceutical sciences.

[38]  T. Kissel,et al.  Heterogeneity in the human intestinal cell line Caco-2 leads to differences in transepithelial transport , 1995 .

[39]  P. Sinko,et al.  Oral absorption of anti-acquired immune deficiency syndrome nucleoside analogues. 2. Carrier-mediated intestinal transport of stavudine in rat and rabbit preparations. , 1996, Journal of pharmaceutical sciences.

[40]  C. J. Blaey,et al.  Effect of pH, buffer concentration and buffer composition on the absorption of theophylline from the small intestine of the rat , 1984 .

[41]  T. Kararli Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals , 1995, Biopharmaceutics & drug disposition.

[42]  K. Luthman,et al.  Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. , 1998, Journal of medicinal chemistry.

[43]  L. Dittert,et al.  Drug absorption. I. An in situ rat gut technique yielding realistic absorption rates. , 1969, Journal of pharmaceutical sciences.

[44]  Peter C. Jurs,et al.  Prediction of Human Intestinal Absorption of Drug Compounds from Molecular Structure , 1998, J. Chem. Inf. Comput. Sci..

[45]  H Lennernäs,et al.  Membrane transport of drugs in different regions of the intestinal tract of the rat. , 1998, Journal of pharmaceutical sciences.

[46]  William Francis Ganong,et al.  Review of Medical Physiology , 1969 .

[47]  J. Lin,et al.  Species similarities and differences in pharmacokinetics. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[48]  R. Borchardt The application of cell culture systems in drug discovery and development. , 1995, Journal of drug targeting.