Prediction of drug absorption based on immobilized artificial membrane (IAM) chromatography separation and calculated molecular descriptors.

The aim of this study was to evaluate the usefulness of IAM chromatography in building a model that would allow prediction of drug absorption in humans. The human intestinal absorption values (%HIA) for 52 drugs with low to high intestinal absorption were collected from the literature. The retention (capacity factor, k') of each drug was measured by reverse-phase HPLC using an IAM.PC.DD2 column (prepared with phosphatidylcholine analogs, 12 microM, 300A, 15 cm x 4.6 mm) with an eluent of acetonitrile-0.1M phosphate buffer at pH 5.4. In addition, 76 molecular descriptors and solubility parameters for each drug were calculated using ChemSW from the 3D-molecular structures. Stepwise regression was employed to develop a regression equation that would correlate %HIA with molecular descriptors and k'. Human intestinal absorption was reciprocally correlated to the negative value of the capacity factor (-1/k') (R=0.64). The correlation was further improved with the addition of molecular descriptors representing molecular size and shape (molecular width, length and depth) solubility (solubility parameter, HLB, hydrophilic surface area) and polarity (dipole, polar surface area) (R=0.83). Experimentally measured IAM chromatography retention values and calculated molecular descriptors and solubility parameters can be used to predict intestinal absorption of drugs in humans. Developed QSAR can be used as a screening method in the designing of drugs with appropriate IA and for the selection of drug candidates in the early stage of drug discovery process.

[1]  Gilles Klopman,et al.  Computer Aided Olive Oil-Gas Partition Coefficient Calculations , 1997, J. Chem. Inf. Comput. Sci..

[2]  D. V. Krevelen,et al.  Properties of polymers : correlations with chemical structure , 1972 .

[3]  W. Rapeport.  Clinical Pharmacokinetics of Bretylium , 1985, Clinical pharmacokinetics.

[4]  R. Schall,et al.  Comparison of the pharmacokinetic profiles of soluble aspirin and solid paracetamol tablets in fed and fasted volunteers. , 2000, Current medical research and opinion.

[5]  S Agatonovic-Kustrin,et al.  Theoretically-derived molecular descriptors important in human intestinal absorption. , 2001, Journal of pharmaceutical and biomedical analysis.

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

[7]  W. R. Carper,et al.  Effects of hydration on the molecular structure of metal ion–atrazine dimer complexes: a MOPAC (PM3) study , 2000 .

[8]  L. Hall,et al.  Molecular connectivity in chemistry and drug research , 1976 .

[9]  A. Leo,et al.  Substituent constants for correlation analysis in chemistry and biology , 1979 .

[10]  F. Burden.  A CHEMICALLY INTUITIVE MOLECULAR INDEX BASED ON THE EIGENVALUES OF A MODIFIED ADJACENCY MATRIX , 1997 .

[11]  P. Swaan,et al.  Mapping the binding site of the small intestinal peptide carrier (PepT1) using comparative molecular field analysis. , 1998, Receptors & channels.

[12]  N. Trinajstic.  Chemical Graph Theory , 1992 .

[13]  M. N. Musa.  Nonlinear Kinetics of Trimipramine in Depressed Patients , 1989, Journal of clinical pharmacology.

[14]  Comparison of structure-activity relationships derived from two methods for estimating octanol-water partition coefficients. , 1996, SAR and QSAR in environmental research.

[15]  R. Kaliszan,et al.  Retention of barbituric acid derivatives on immobilized artificial membrane stationary phase and its correlation with biological activity. , 2000, Biomedical chromatography : BMC.

[16]  R A Morrison,et al.  Current methodologies used for evaluation of intestinal permeability and absorption. , 2000, Journal of pharmacological and toxicological methods.

[17]  J. Legendre,et al.  Determination of the passive absorption through the rat intestine using chromatographic indices and molar volume. , 2001, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[18]  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.

[19]  Kristina Luthman,et al.  Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans , 1997, Pharmaceutical Research.

[20]  R. van der Meer,et al.  UvA-DARE ( Digital Academic Repository ) Differential in vivo and in vitro intestinal permeability to lactulose and mannitol in animals and humans : a hypothesis , 2004 .

[21]  B. Brodie,et al.  SOME PHYSICO‐CHEMICAL FACTORS IN DRUG ACTION , 1957, The Journal of pharmacy and pharmacology.

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

[23]  R. Johansson,et al.  Plasma levels of imipramine and desipramine in man after different routes of administration , 2004, Naunyn-Schmiedeberg's Archives of Pharmacology.

[24]  G Beck,et al.  Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. , 2001, Journal of pharmaceutical sciences.

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

[26]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[27]  Han van de Waterbeemd,et al.  Lipophilicity in PK design: methyl, ethyl, futile , 2001, J. Comput. Aided Mol. Des..

[28]  Hao Zhu,et al.  Estimation of the Aqueous Solubility of Organic Molecules by the Group Contribution Approach , 2001, J. Chem. Inf. Comput. Sci..

[29]  P. Hansen,et al.  Alkanes with small and large Randić connectivity indices , 1999 .

[30]  P. Selzer,et al.  Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. , 2000, Journal of medicinal chemistry.

[31]  C. Pidgeon,et al.  Immobilized-artificial-membrane chromatography: measurements of membrane partition coefficient and predicting drug membrane permeability. , 1996, Journal of chromatography. A.

[32]  Milan Randic,et al.  Novel Shape Descriptors for Molecular Graphs , 2001, J. Chem. Inf. Comput. Sci..

[33]  Arup K. Ghose,et al.  Atomic physicochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics , 1989, J. Chem. Inf. Comput. Sci..

[34]  K. Stoschitzky,et al.  Stereoselective increase of plasma concentrations of the enantiomers of propranolol and atenolol during exercise , 1995, Clinical pharmacology and therapeutics.

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

[36]  John Shorter,et al.  Correlation analysis of organic reactivity, with particular reference to multiple regression , 1982 .

[37]  P Buchwald,et al.  Octanol-water partition: searching for predictive models. , 1998, Current medicinal chemistry.

[38]  C. Pidgeon,et al.  Phospholipid immobilization on solid surfaces. , 1994, Analytical chemistry.

[39]  R. Guy,et al.  The influence of molecular volume and hydrogen-bonding on peptide transport across epithelial membranes. , 1993, Pharmaceutical research.