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Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine

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Abstract

Based on its lower Log P value relative to metoprolol, a marker for the low/high-permeability (P eff) class boundary, pseudoephedrine was provisionally classified as BCS low-permeability compound. On the other hand, following oral administration, pseudoephedrine fraction dose absorbed (F abs) and systemic bioavailability approaches 100%. This represents a challenge to the generally recognized P eff–F abs correlation. The purpose of this study was to elucidate the underlying mechanisms behind the confusion in pseudoephedrine’s BCS classification. Pseudoephedrine’s BCS solubility class was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in vitro and in vivo in rats, considering the complexity of the whole of the small intestine. Pseudoephedrine was found to be unequivocally a high-solubility compound. All of the permeability studies revealed similar phenomenon; at any given intestinal segment/pH, the permeability of metoprolol was higher than that of pseudoephedrine, however, as the intestinal region becomes progressively distal, and the pH gradually increases, pseudoephedrine’s permeability rises above that of metoprolol in the former segment. This unique permeability pattern likely explains pseudoephedrine’s complete absorption. In conclusion, pseudoephedrine is a BCS Class I compound; no discrepancy between P eff and F abs is involved in its absorption. Rather, it reflects the complexity behind P eff when considering the whole of the intestine. We propose to allow high-permeability classification to drugs with P eff that matches/exceeds the low/high class benchmark anywhere throughout the intestinal tract and not restricted necessarily to the jejunum.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer-Sheva, 84105, Israel

    Moran Fairstein, Rotem Swissa & Arik Dahan

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  1. Moran Fairstein
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  2. Rotem Swissa
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  3. Arik Dahan
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Correspondence to Arik Dahan.

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Fairstein, M., Swissa, R. & Dahan, A. Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine. AAPS J 15, 589–597 (2013). https://doi.org/10.1208/s12248-013-9462-x

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