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

Abstract

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.

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

“…The PAMPA studies were carried out in 96-well MultiScreen Permeability Filter Plate obtained from Millipore Co. (Billerica, MA), using the hexadecane method described previously [30], with some modifications [31], [32]. Briefly, each well was impregnated with 15 µL of 5% hexadecane dissolved in n-hexane for 1 hr to allow complete evaporation of the hexane.…”

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Codeine Phosphate

“…In general, a reasonable correlation exists between log P values and jejunal permeability; however, a significant number of false‐negative cases have been recorded, in which drugs with lower log P than metoprolol exhibit complete absorption. These include antipyrine, cephalexin, d ‐glucose, levodopa, l ‐leucine, phenylalanine, piroxicam, valacyclovir, pseudoephedrine, and sotalol, indicating the difficulty of assigning BCS classification based merely on limited physicochemical characteristics.…”

“…To account for the complexity of the whole of the small intestine, permeability was determined in three different 10‐cm segments: a proximal jejunal segment, mid‐small intestinal segment, and a distal ileal segment . Briefly, each intestinal segment was cannulated on two ends, and was perfused with the corresponding phosphate buffer containing codeine and metoprolol.…”

“…[18][19][20] To account for the complexity of the whole of the small intestine, permeability was determined in three different 10-cm segments: a proximal jejunal segment, mid-small intestinal segment, and a distal ileal segment. [21][22][23] Briefly, each intestinal segment was cannulated on two ends, and was perfused with the corresponding phosphate buffer containing codeine and metoprolol. The concentrations of codeine and metoprolol in the perfusion buffers were 240 and 400 :g/mL, respectively, to represent the maximal dose of the drugs (60 and 100 mg, respectively) in 250 mL.…”

Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility–Permeability Interplay

“…Carbamazepine solubility was measured at increasing concentrations (0–40% w/v) of hydrotrope (urea vs. nicotinamide) in 10 mM MES buffer, pH 6.5, at room temperature (25°C) and at 37°C as described previously (Fairstein et al, 2013; Zur et al, 2014a). Briefly, excess of drug powder was incubated with different urea/nicotinamide solutions (0–40% w/v) for 24–48 h, followed by centrifugation, supernatant withdrawal, filtration, and UPLC analysis for drug content.…”