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

The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F_abs) in humans is 90% or higher. This direct correlation between human permeability and F_abs has been recently controversial, since the β-blocker sotalol showed high F_abs (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F _abs. The effective permeabilities (P_eff) of sotalol and metoprolol, a FDA standard for the low/high P_eff class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P _eff at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK_a and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol-buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P_eff value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6.5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high F_abs. In conclusion, we have shown that, in fact, there is no discrepancy between P_eff and F_abs in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.