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Factors Influencing Drug Absorption: Physicochemical Parameters01:22

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The physicochemical characteristics of drugs play a crucial role in formulating stable and bioavailable drug products. The solubility of a drug, governed by the varying pH along the GI tract and its dissociation constant (pKa), is pivotal in determining its ionization state and absorption rate. Notably, weak acids and bases remain unionized and are absorbed more rapidly.
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Factors Influencing Drug Absorption: Drug Dissolution01:27

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The pharmacokinetic journey of drugs from solid oral dosage forms into systemic circulation is multifaceted. It begins with disintegration, a prerequisite ensuring a solid dosage form's subdivision into minute particles. Dissolution occurs next as these granulated entities solubilize in gastrointestinal fluids. This solubilization is crucial for the succeeding stage, permeation, which describes the traversal of the drug across the intestinal membrane and its subsequent entry into the blood...
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Drug absorption within the gastrointestinal (GI) tract is a complex process influenced by several critical factors, including the site pH, the drug's dissociation constant (pKa), and the drug's lipophilicity. The GI tract exhibits a pH gradient, with an acidic environment in the stomach and a more alkaline environment in the small intestine. This pH variation directly affects the ionization state of drugs.
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Orally administered drugs primarily enter the systemic circulation via passive diffusion through the intestinal membranes. The drug's absorption is influenced by drug stability in the gastrointestinal GI tract, membrane permeability, the surface area available for absorption, luminal drug concentration, and residence time in the lumen. Drug permeability can be enhanced by adjusting the lipophilicity, polarity, or molecular size of the drug, promoting its passive transport across intestinal...
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Drug absorption involves the movement of drugs from the point of administration into the systemic circulation. Initially, Gastrointestinal (GI) motility propels the drug through the digestive tract and into the stomach. However, the stomach's high acidity and limited surface area restrict its role in drug absorption for most drugs. The drug then moves from the stomach to the small intestine via gastric emptying, which can be slowed by various factors, including interactions with other...
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Non-oral extravascular routes, which encompass sublingual, buccal, topical, intramuscular, and inhalation methods, primarily utilize passive diffusion to transport drugs into the systemic circulation. The absorption rates and effectiveness of these routes depend on the drug's physicochemical properties, as well as the patient's anatomical and pathophysiological state.
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Predicting Oral Absorption for Compounds Outside the Rule of Five Property Space.

Felix Huth1, Norbert Domange1, Birk Poller1

  • 1Pharmacokinetic Sciences, Novartis Institutes for BioMedical Research, Basel, Switzerland.

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Summary

This study enhances oral drug absorption prediction by modifying transwell assays. Adding albumin to the assay improves accuracy for larger molecules, aiding drug discovery efforts.

Keywords:
BSAFraction absorbedLipophilic compoundsLysosomal trappingMDCKP-gp knockoutPermeability

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Area of Science:

  • Pharmacology
  • Drug Discovery
  • Biophysical Chemistry

Background:

  • Accurate prediction of oral drug absorption is crucial for drug discovery.
  • Traditional cell-based transwell assays predict in vivo absorption but struggle with larger or lipophilic molecules.
  • Limitations include cellular binding and lysosomal trapping, affecting prediction accuracy.

Purpose of the Study:

  • To modify the transwell permeability assay for improved prediction of oral drug absorption.
  • To address limitations in evaluating larger molecules and lipophilic bases.
  • To enhance the predictive power of transwell assays for drug candidates.

Main Methods:

  • Modification of the standard transwell permeability assay.
  • Addition of albumin to the acceptor compartment to mitigate drug-cell and drug-medium interactions.
  • Utilizing compounds with known passive permeation mechanisms for calibration.

Main Results:

  • The modified assay, with albumin, significantly improved the prediction of drug absorption.
  • Reduced cellular binding and lysosomal trapping were observed for larger, lipophilic molecules.
  • Higher recovery values and enhanced predictive power were achieved under more physiological conditions.
  • Lysosomal trapping was found to be an exception rather than a general rule for lipophilic bases.

Conclusions:

  • The albumin-supplemented transwell assay offers superior predictive capability for oral drug absorption, especially for challenging molecules.
  • This enhanced assay provides a more reliable method for selecting drug candidates in medicinal chemistry.
  • The findings suggest a more accurate assessment of fraction absorbed for diverse drug molecules.