Abstract

BackgroundUnderstanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations.MethodsGiven the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function (“Averaged Model” (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface.ResultsTheoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4.ConclusionsThe AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models.

Highlights

  • Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs

  • This paper describes a new approach to measuring human intestinal permeability during normal drug absorption

  • Since the concentration profile has a strong dependence on TD, these plots could be used to estimate the value of TD in the human if experimental measurements of the concentration profile along the small intestine for impermeable solutes were available

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Summary

Introduction

Understanding the quantitative relationship between a drug’s physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations. Despite the multitude of publications describing the different factors that affect the rate of intestinal absorption of drugs, there is only limited experimental data for the human small intestinal permeability of the thousands of drugs that are orally absorbed. The quantitative structure activity relationship (QSAR) between a drug’s physical chemical properties and its rate of intestinal absorption is obviously of great importance in selecting candidate drugs. The standard approach is to relate some property of the drug (e.g. octanol/water partition, Caco-2 cell permeability, etc.) to the fraction absorbed in humans [1,2]. The fraction absorbed may be influenced in uncertain ways by factors such as intestinal metabolism or large intestinal absorption

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