High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations

Abstract

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.

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…unstirred water layer (UWL) permeation, transcellular permeation, paracellular permeation and/or carried-mediated absorption/efflux (2,(17)(18)(19). In addition, jejunal P eff can be affected by the experimental conditions and the physiological factors that the drug might encounter during its passage through the intestinal membrane in the upper jejunum (3,12,20).…”

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

“…Pseudoephedrine hence represents a case of disagreement between the BCS and the BDDCS, and a deviation from the P eff -F met (fraction metabolized) correlation proposed by the BDDCS. Thus, while the extent of drug metabolism may be useful in supporting permeability classification under certain circumstances, the data presented in this paper demonstrate the care that must be taken with intestinal permeability/extent of absorption determinations (12,24,44).…”

“…5), and by previous reported studies ( [41][42][43]. The increasing pH along the intestine may result in this unique absorption pattern for a whole class of molecular entities; we have previously shown that the β-blocker sotalol follows a similar permeability pattern, starting as lowpermeability in the proximal GI sections, increasing gradually with the pH increase throughout the small intestine, and becomes a high-permeability compound as the pH rises above 7.5 in the ileum, which allows for complete absorption of this drug (24). While pseudoephedrine includes the basic secondary amine as a sole ionizable center, sotalol is an amphoteric molecule that contains the acidic methanesulfonamide functionality and the basic secondary amine.…”

“…The permeability in each intestinal segment was measured at the pH that corresponds to the physiological pH of that region: (1) proximal jejunum, pH 6.5; (2) mid-small intestine, pH 7.0; and (3) distal ileum, pH 7.5 (24,25). The perfusion buffer was first perfused for 1 h, to ensure steady-state conditions, followed by additional 1 h of perfusion with samples taken every 10 min.…”

Biomimetic PVPA in vitro model for estimation of the intestinal drug permeability using fasted and fed state simulated intestinal fluids

“…Another factor that may influence the apparent permeability of the drug compounds is the relation between the drugs pKa values and the pH of the different media. One has thus to consider that the intestinal permeability along the GI tract could be pH dependent, since pH might influence the drugs' charge state, and further affect the drug absorption in a more complex manner (Dahan et al, 2010;Lennernäs, 2014).…”