Humans intestinal data

Zhao YH, LeJ, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Boutina D, Beck G, Sherborne B, Cooper J, and Platts JA. Evaluation of Human Intestinal Data and Subsequent Derivation of a Quantitative Structure-Activity Relationship (QSAR) with the Abraham Descriptors./P/tarro Sci 2001 90 749-784. 

A volume-related term (expressed by polarizability) and electrostatics (expressed by partial atomic charge) made minor contributions to intestinal absorption in humans. Lipophilicity, expressed by logP or logD values, shows no correlation with the human absorphon data. Recently, similar results were obtained for 154 passively transported drugs on the basis of surface thermodynamics descriptors [39] ... 

C. N., Boutina, D., Beck, G., Sherbom, B., Cooper, J., Platts, J. A. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structure-activity relationship (QSAR) with the Abraham descriptors. J. Pharm. Sci. 2001, 90, 749-784. 

The CAT model considers passive absorption, saturable absorption, degradation, and transit in the human small intestine. However, the absorption and degradation kinetics are the only model parameters that need to be determined to estimate the fraction of dose absorbed and to simulate intestinal absorption kinetics. Degradation kinetics may be determined in vitro and absorption parameters can also be determined using human intestinal perfusion techniques [85] therefore, it may be feasible to predict intestinal absorption kinetics based on in vitro degradation and in vivo perfusion data. Nevertheless, considering the complexity of oral drug absorption, such a prediction is only an approximation. 

Walter, E., Kissel, T., Reers, M., Dickneite, G., Hoffmann, D., Stuber, W., Transepithelial transport properties of peptidomimetic thrombin inhibitors in monolayers of a human intestinal cell line (Caco-2) and their correlation to in vivo data, Pharm. Res. 1995, 32, 360-365. 

Overall, in this chapter we have attempted to emphasize the need for more in vivo studies to be conducted to clarify the dynamic interplay between mechanisms of drug transport and metabolism in the human intestine under in vivo conditions. There is also a need to develop additional in vivo techniques for direct measurements of these processes in regions along the GI tract in humans, and to relate the findings to various physiological/pathophysiological conditions. This would clearly increase our knowledge of the mechanisms involved, and provide in vivo data to help develop and validate rapid and reliable in vitro intestinal models. 

Xanthophyll esters are common in fruits and vegetables. Few data exist regarding the effect of carotenoid esterification on carotenoid bioavailability. Xanthophyll esters are readily broken in the human intestine (West and Castenmiller 1998 Breithaupt and others 2003 Faulks and Southon 2005). Chitchumroonchokchai and Failla (2006) demonstrated that hydrolysis of zeaxanthin esters increases zeaxanthin bioavailability. Wingerath and others (1995) did not find (3-cryptoxanthin esters in chylomicrons from humans fed with tangerine juice. Herbst and others (1997) demonstrated that lutein diesters are more bioavailable than free lutein. However, the question of whether the free or the esterified form is more bioavailable to humans is still an ongoing discussion. 

The basis for all CAT models is the fundamental understanding of the transit flow of drugs in the gastrointestinal tract. Yu et al. [61] compiled published human intestinal transit flow data from more than 400 subjects, and their work showed the human mean small intestinal transit time to be 199 min. and that seven compartments were optimal in describing the small intestinal transit process using a compartmental approach. In a later work, Yu et al. [58] showed that between 1 and 14 compartments were needed to optimally describe the individual small intestine transit times in six subjects but in agreement with the earlier study, the mean number of compartments was found to be seven. This compartmental transit model was further developed into a compartmental absorption and transit (CAT) model ([60], [63]). The assumptions made for this CAT model was that no absorption occurs in the stomach or in the colon and that dissolution is instantaneous. Yu et al. [59] extended the CAT model... 

Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, Beck G, Sherborne B, Cooper I (2003) Evaluation of rat intestinal absorption data and correlation with human intestinal absorption. Eur. J. Med. Chem. 38 233-243. 

VolSurf was also successfully applied in the literature to predict absorption properties [156] from experimental drug permeability data of 55 compounds [165] in Caco-2 cells (human intestinal epithelial cell line derived from a colorectal carcinoma) and MDCK cell monolayers (Madin-Darby canine kidney). In this interesting case, it was shown that models including counterions for charged molecules clearly show significantly better quality and overall performance. The final model was also able to correctly predict, to a great extent, the relative ranking of molecules from another Caco-2 permeability study by Yazdanian et al. ]166]. 

There are three main sources of evidence for pro-tumorigenic activity of bile acids in the lower gastro-intestinal tract (activity in rodent CRC models, human observational data and mechanistic studies using CRC cells in vitro), which together create a strong case for a role for colorectal mucosal bile acid exposure during human colorectal carcinogenesis. 

Unfortunately the number of in silica modeling studies on brain membrane permeability is significantly smaller than for human intestinal absorption, resulting in a lack of consensus about how to assess brain penetration (both in vitro and in vivo) and the intrinsic difficulty of measuring this particular endpoint, which overall results in a low turnover of data generation that could be used to build in silica models [95, 96]. For this reason, the in silica models used to assess brain permeability in the discovery process focus normally on P-gp efflux and some measure of in vitro membrane permeability, methods which are reviewed in the next section. 

The authors defined a new absorption potential , APS(JV, to describe human intestinal absorption data. It is defined in Eq. 4.5 and listed in Table 4.1. 

Caco-2 cells, especially the human intestinal epithelial cell line, have been proposed and used for the simulation and prediction of intestinal drug absorption after oral administration. These membranes of cells have useful properties for correlation with in vivo data such as enzymatic and transporter systems [24]. 

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