Prediction of drug absorption based on Immobilized Artificial membrane (IAM) chromatography separation and calculated molecular descriptors
Yen, T.E., Agatonovic-Kustrin, S., Evans, A.M., Nation, R.L., and Ryand, J. (2005) Prediction of drug absorption based on Immobilized Artificial membrane (IAM) chromatography separation and calculated molecular descriptors. Journal of Pharmaceutical and Biomedical Analysis, 38 (3). pp. 472-478.
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The aim of this study was to e valuate 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 μM, 300 Å, 15 cm × 4.6 mm) with an eluent of acetonitrile–0.1 M 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.
|Item Type:||Article (Refereed Research - C1)|
|Keywords:||IAM chromatography, drug absorption, molecular descriptors, QSAR|
|Date Deposited:||07 Sep 2009 03:21|
|FoR Codes:||11 MEDICAL AND HEALTH SCIENCES > 1115 Pharmacology and Pharmaceutical Sciences @ 75%
11 MEDICAL AND HEALTH SCIENCES > 1104 Complementary and Alternative Medicine @ 25%
|Citation Count from Web of Science||