High-permeability criterion for BCS classification: segmental/pH dependent permeability considerations.

Area of Science:

• Pharmacokinetics and Drug Absorption
• Physicochemical Properties of Drugs
• Gastrointestinal Physiology

Background:

• The FDA defines high-permeability drugs by F(abs) ≥ 90%.
• Sotalol's high F(abs) contradicts its low Caco-2 permeability, creating a controversial correlation.
• Understanding this disparity is crucial for accurate drug classification.

Purpose of the Study:

• To investigate the scientific basis for the observed discrepancy between drug permeability and F(abs).
• To evaluate the effective permeability (P(eff)) of sotalol and metoprolol across different intestinal pH environments.
• To clarify the mechanism linking physicochemical properties to intestinal absorption.

Main Methods:

• Utilized a rat perfusion model to measure P(eff) of sotalol and metoprolol in jejunum (pH 6.5), mid-intestine (pH 7.0), and ileum (pH 7.5).
• Performed physicochemical analysis including ionization, pK(a), and partitioning (octanol-buffer experiments).
• Compared experimental P(eff) values with established F(abs) data and FDA permeability standards.

Main Results:

• Both drugs exhibited pH-dependent permeability, increasing with higher pH.
• Sotalol consistently showed lower P(eff) than metoprolol at equivalent pH.
• Sotalol's P(eff) at pH 7.5 met or exceeded metoprolol's P(eff) at pH 6.5 and 7.0, aligning with its high F(abs).

Conclusions:

• The study resolves the sotalol permeability-F(abs) discrepancy, demonstrating that high F(abs) correlates with high permeability at relevant intestinal pH.
• Effective permeability is region- and pH-dependent, with higher pH in the distal ileum being critical for sotalol's absorption.
• The findings emphasize the importance of considering the entire intestinal tract's physiological conditions for drug absorption assessment.