| 2. |
- Dahan, Arik, et al.
(författare)
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High-Permeability Criterion for BCS Classification : Segmental/pH Dependent Permeability Considerations
- 2010
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Ingår i: Molecular pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 7:5, s. 1827-1834
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Tidskriftsartikel (refereegranskat)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 Fab, has been recently controversial, since the beta-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-off 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 Faros, 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.
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| 3. |
- Dahan, Arik, et al.
(författare)
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The Fraction Dose Absorbed, in Humans, and High Jejunal Human Permeability Relationship
- 2012
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 9:6, s. 1847-1851
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Tidskriftsartikel (refereegranskat)abstract
- The drug intestinal permeability (P-eff) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (F-abs) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo Puff measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding F-abs and P-err in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal P-eff as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejunal P-eff will have high F-abs, eliminating the risk for misclassification as a BCS class I drug. Much more care should be taken, however, when jejunal P-eff does not support a high-permeability classification; a thorough examination may reveal high-permeability after all, attributable to e.g. segmental-dependent permeability due to degree of ionization or transporter expression. In this situation, the use of multiple permeability experimental methods, including the use of metabolism, which except for huminal degradation requires absorption, is prudent and encouraged.
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