Control of Intestinal Permeability

Chemistry control of intestinal permeability via passive tran -cellular processes is poor. The good news is that, in general, poor permeability is not a problan in combinatorial libraries. One really has to go out of one s way to introduce enough polar functionality in a combinatorial compound to 

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Chemistry control of intestinal permeability is poor. The good news is that, in general, poor permeability is not a problem in combinatorial libraries. One really has to go out of one s way to introduce enough polar functionality in a combinatorial compound to make a compound impermeable via passive rran -cellular processes (the most common absorptive pathway). The bad news is that if a compound has poor intestinal permeability there is virtually nothing to fix the problem in terms of pharmaceutical formulation technology. Chemistry control of intestinal permeability is poor because, except for a few very specific exceptions, chemistry SAR is blunt. 

Peniche et al. (2004) successfully encapsulated up to 65 % of shark liver oil (rich in polyunsaturated fatty acids) in chitosan/alginate capsules in order to mask the oil s unpleasant taste. Here again it was found that the chitosan coating allowed a greater degree of control of capsule permeability. The capsules could be degraded by enzymes such as lipase or pancreatin. They were initially resistant to the acid environment of the stomach, although after 4 hours under intestinal conditions (pH = 7.4) the capsule walls were finally disrupted. 

Various in vitro and in vivo methods have been used to predict drug absorption including Caco-2 cells, in situ intestinal permeability, whole-animal studies, and more recently chromatographic methods. Compared with in vivo absorption studies, evaluation of intestinal permeability in vitro requires less compound is relatively easy to study, often avoiding complicated surgery is rapid and can allow a wider variety of variables to be controlled. ... 

Stenberg, P., Luthman, K., Artursson, P. Virtual screening of intestinal drug permeability. J. Control. Rel. 2000, 65, 231-243. 

Dowty, M. E. Dietsch, C. R., Improved prediction of in vivo peroral absorption from in vitro intestinal permeability using an internal standard to control for intra- inter-rat variability, Pharm. Res. 14, 1792-1797 (1997). 

E Lipka, LX Yu, D Liu, JR Crison, GL Amidon. Evaluation of the intestinal permeability of (3-blocker drugs and their potential for oral controlled release. Proc Int Symp Controlled Release Bioact Mater 22 366-367, 1995. 

Aqueous solubility, potency and permeability are three factors under medicinal chemistry control that must be optimized to achieve a compound with acceptable oral absorption. Typically, a lead (chemistry starting point) is deficient in all three parameters. The inter-relationships of these three parameters has been described in a series of publications from Pfizer researchers [7, 8]. Figure 9.1 depicts graphically the minimum acceptable solubility as a function of projected clinical potency and intestinal permeability. A minimum thermodynamic aqueous solubility of 52... 

Kotze AF, Leeuw BJ, Luessen HL, Boer AG, Verhoef JC, Junginger HE (1998) Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Control Release 51 35—46. 

Johnson KC (2003) Dissolution and absorption modeling Model expansion to simulate the effect of precipitation, water absorption, longitudinally changing intestinal permeability, and controlled release on drug absorption. Drug Dev. Ind. Pharm. 29 833-842. 

Grass et al. [69] evaluated the performance of controlled release dosage forms of the anti-thrombic drug ticlopidine using computer simulations based on data from in vitro intestinal permeability studies in various sections of the intestine of rabbit and monkey. 

The CAT model presupposes that dissolution is instantaneous and therefore the kinetics of the permeation step control the gastrointestinal absorption of drug. This is reflected in the previous equation, which indicates that the effective permeability is the sole parameter controlling the intestinal absorption of highly soluble drugs. 

The main functions of the GI - digestion and absorption of nutrients, vitamins and cofactors as well as movements of ions and water - need a precise mechanisms of biochemical and physiological control to maintain barrier functions. The cells in the intestine are characterized by high enzymatic activity (lumen and wall), low permeability and typical resistance (between cells tight junctions are formed characterizing the very thight barriers in the organism), efflux pathways back into the gut lumen and first-pass metabolism. The barrier function of the gut is a crucial prerequisite for a normal function of intestine. Impairments lead to diarrhoea and other serious consequences. 

Johnson KC. Dissolution and Absorption Modeling Model Expansion to Simulate the Effects of Precipitation, Water Absorption, Longitudinally Changing Intestinal Permeability, and Controlled Release on Drug Absorption. Drug Devloplnd Pharm 2003 29 833-842. 

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