Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine
Regional-Dependent Intestinal Permeability and BCS Classification: Elucidation of pH-Related Complexity in Rats Using Pseudoephedrine
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DOI：
10.1208/s12248-013-9462-x
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发表时间：
2013-04-01
期刊：
影响因子：
4.5
通讯作者：
Dahan, Arik
中科院分区：
文献类型：
--
作者：
Fairstein, Moran;Swissa, Rotem;Dahan, Arik
基于其相对于美托洛尔的较低Log P值（低/高渗透性（P（eff））类别边界的标志物），伪麻黄碱被暂时归类为BCS低渗透性化合物。另一方面，口服给药后，伪麻黄碱的吸收剂量分数（F（abs））和全身生物利用度接近100%。这代表了对通常公认的P（eff）-F（abs）相关性的挑战。本研究的目的是阐明伪麻黄碱BCS分类混乱背后的潜在机制。考虑到整个小肠的复杂性，测定了伪麻黄碱的BCS溶解度等级，并在体外和大鼠体内对其理化性质和肠渗透性进行了彻底研究。伪麻黄碱被认为是明确的高溶解度化合物。所有的渗透性研究均显示了类似的现象;在任何给定的肠段/pH下，美托洛尔的渗透性均高于伪麻黄碱，然而，随着肠区逐渐变远，pH值逐渐升高，伪麻黄碱的渗透性在前一段中高于美托洛尔。这种独特的渗透模式可能解释了伪麻黄碱的完全吸收。总之，伪麻黄碱是BCS I类化合物; P（eff）和F（abs）之间没有差异涉及其吸收。相反，它反映了考虑整个肠道时P（eff）背后的复杂性。我们建议允许高渗透性分类的药物与P（eff）匹配/超过低/高类基准在整个肠道的任何地方，而不一定限于空肠。
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.