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Rate-Limited Steps of Human Oral Absorption and QSAR Studies

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Abstract

Purpose. To classify the dissolution and diffusion rate-limited drugs and establish quantitative relationships between absorption and molecular descriptors.

Methods. Absorption consists of kinetic transit processes in which dissolution, diffusion, or perfusion processes can become the rate-limited step. The absorption data of 238 drugs have been classified into either dissolution or diffusion rate-limited based on an equilibrium method developed from solubility, dose, and percentage of absorption. A nonlinear absorption model derived from first-order kinetics has been developed to identify the relationship between percentage of drug absorption and molecular descriptors.

Results. Regression analysis was performed between percentage of absorption and molecular descriptors. The descriptors used were ClogP, molecular polar surface area, the number of hydrogen-bonding acceptors and donors, and Abraham descriptors. Good relationships were found between absorption and Abraham descriptors or ClogP.

Conclusions. The absorption models can predict the following three BCS (Biopharmaceutics Classification Scheme) classes of compounds: class I, high solubility and high permeability; class III, high solubility and low permeability; class IV, low solubility and low permeability. The absorption models overpredict the absorption of class II, low solubility and high permeability compounds because dissolution is the rate-limited step of absorption.

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Authors and Affiliations

  1. Department of Chemistry, University College London, 20 Gordon Street, London, WC1H 0AJ, United Kingdom

    Yuan H. Zhao, Michael H. Abraham & Joelle Le

  2. DMPK, Mechanism and Extrapolation Technologies, GlaxoSmithKline, Park Road, Ware, SG12 0DP, United Kingdom

    Anne Hersey & Chris N. Luscombe

  3. Roche Products Ltd, Welwyn Garden city, Herts, AL7 3AY, United Kingdom

    Gordon Beck, Brad Sherborne & Ian Cooper

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  1. Yuan H. Zhao
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  2. Michael H. Abraham
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  3. Joelle Le
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  4. Anne Hersey
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  5. Chris N. Luscombe
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  7. Brad Sherborne
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  8. Ian Cooper
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Correspondence to Michael H. Abraham.

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Zhao, Y.H., Abraham, M.H., Le, J. et al. Rate-Limited Steps of Human Oral Absorption and QSAR Studies. Pharm Res 19, 1446–1457 (2002). https://doi.org/10.1023/A:1020444330011

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