Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability.

To evaluate absorption of compounds across the membrane via a transcellular route, the permeability of peptide derivatives and related compounds was measured by the parallel artificial membrane permeation assay (PAMPA). The permeability coefficients by PAMPA were analyzed quantitatively using classical QSAR and Volsurf approaches with the physicochemical parameters. The results from both approaches showed that hydrogen bonding ability of molecules in addition to hydrophobicity at a particular pH were significant in determining variations in PAMPA permeability coefficients. The relationship between Caco-2 cell permeability and artificial lipid membrane permeability was then determined. The compounds were sorted according to their absorption pathway in the plot of the Caco-2 cell and PAMPA permeability coefficients.

[1]  Yi Han,et al.  Predicting Caco-2 Cell Permeation Coefficients of Organic Molecules Using Membrane-Interaction QSAR Analysis , 2002, J. Chem. Inf. Comput. Sci..

[2]  K. Luthman,et al.  Correlation of drug absorption with molecular surface properties. , 1996, Journal of pharmaceutical sciences.

[3]  I Moriguchi,et al.  Non-congeneric structure-pharmacokinetic property correlation studies using fuzzy adaptive least-squares: oral bioavailability. , 1994, Biological & pharmaceutical bulletin.

[4]  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.

[5]  J. Riordan,et al.  The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. , 1986, Biochemical and biophysical research communications.

[6]  B. Faller,et al.  High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. , 2001, Journal of medicinal chemistry.

[7]  C. Pidgeon,et al.  IAM chromatography: an in vitro screen for predicting drug membrane permeability. , 1995, Journal of medicinal chemistry.

[8]  P. Carrupt,et al.  Molecular fields in quantitative structure–permeation relationships: the VolSurf approach , 2000 .

[9]  D. B. Boyd.  Quantum Chemistry Program Exchange. , 1999, Journal of molecular graphics & modelling.

[10]  M. Machida,et al.  High Throughput Prediction of Oral Absorption: Improvement of the Composition of the Lipid Solution Used in Parallel Artificial Membrane Permeation Assay , 2001, Journal of biomolecular screening.

[11]  Kin-Kai Hwang,et al.  A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. , 2002, European journal of medicinal chemistry.

[12]  M Pastor,et al.  VolSurf: a new tool for the pharmacokinetic optimization of lead compounds. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

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

[14]  Hydrophobicity of N‐Acetyl‐Di‐ and Tripeptide Amides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters , 1990 .

[15]  P. Augustijns,et al.  Use of Caco-2 cells and LC/MS/MS to screen a peptide combinatorial library for permeable structures. , 1999, International journal of pharmaceutics.

[16]  S. Wold,et al.  The Collinearity Problem in Linear Regression. The Partial Least Squares (PLS) Approach to Generalized Inverses , 1984 .

[17]  H. Terada,et al.  Partition and Ion-pair Partition of 2, 4-Dinitrophenol, an Uncoupler of Oxidative Phosphorylation , 1981 .

[18]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[19]  Y. Kanai,et al.  Cloning and Characterization of a Novel Multispecific Organic Anion Transporter * , 1997 .

[20]  T. Vidmar,et al.  Strategies toward predicting peptide cellular permeability from computed molecular descriptors. , 1999, The journal of peptide research : official journal of the American Peptide Society.

[21]  Sean Ekins,et al.  Three-Dimensional Quantitative Structure-Permeability Relationship Analysis for a Series of Inhibitors of Rhinovirus Replication , 2001, J. Chem. Inf. Comput. Sci..

[22]  Han van de Waterbeemd,et al.  Estimation of Caco‐2 Cell Permeability using Calculated Molecular Descriptors , 1996 .

[23]  John G. Topliss,et al.  QSAR Model for Drug Human Oral Bioavailability1 , 2000 .

[24]  T. Fujita,et al.  Hydrophobicity of Di‐ and Tripeptides Having Unionizable Side Chains and Correlation with Substituent and Structural Parameters , 1989 .

[25]  T. Fujita,et al.  Hydrogen-bonding parameter and its significance in quantitative structure--activity studies. , 1977, Journal of medicinal chemistry.

[26]  M. Yazdanian,et al.  Correlating Partitioning and Caco-2 Cell Permeability of Structurally Diverse Small Molecular Weight Compounds , 1998, Pharmaceutical Research.

[27]  A. Berglund,et al.  Structure-property model for membrane partitioning of oligopeptides. , 2000, Journal of medicinal chemistry.

[28]  U Norinder,et al.  Experimental and computational screening models for the prediction of intestinal drug absorption. , 2001, Journal of medicinal chemistry.

[29]  K. Iseki,et al.  Development of a new system for prediction of drug absorption that takes into account drug dissolution and pH change in the gastro-intestinal tract. , 2001, International journal of pharmaceutics.

[30]  M. Hashida,et al.  Prediction of Caco-2 cell permeability using a combination of MO-calculation and neural network. , 2002, International journal of pharmaceutics.

[31]  J. Stewart.  Optimization of parameters for semiempirical methods II. Applications , 1989 .

[32]  Kiyohiko Sugano,et al.  Prediction of passive intestinal absorption using bio-mimetic artificial membrane permeation assay and the paracellular pathway model. , 2002, International journal of pharmaceutics.

[33]  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.