Reducing Human Absorption

The physicochemical properties that affect absorption from the GI tract, skin and lungs are summarized in Table 13.2. 

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Must have reduced human absorption and bioavailability The toxicity of it should be understood Knowledge of its environmental fate is understood Minimized hazardous properties (e.g., explosivity) Minimal chemical effects due to reactivity (e.g., oxidation) Reduced synergism with known environmental toxins... 

In studies of mice, rats, and dogs, diisopropyl methylphosphonate was rapidly absorbed into plasma (Hart 1976). The plasma data indicate that all three species rapidly absorbed diisopropyl methylphosphonate, although the exact rate was species specific. Although no studies were located regarding human absorption, diisopropyl methylphosphonate is also likely to be absorbed rapidly into the plasma of humans. The ability of porous polymeric sorbents, activated carbon, and dialysis to remove diisopropyl methylphosphonate from human plasma has been studied (McPhillips 1983). The grafted butyl-XAD-4 was found to be the most efficient sorbent for the removal of diisopropyl methylphosphonate from human plasma. Hemoperfusion of plasma over synthetic XAD-4 or butyl-XAD-4 sorbent resin was more efficient than dialysis/ultrafiltration for the removal of diisopropyl methylphosphonate from human plasma the smaller surface of the packed resins provided less area to minimize damage to molecular constituents of the plasma. These methods are useful in reducing diisopropyl methylphosphonate concentrations in the plasma. However, since diisopropyl methylphosphonate and its metabolites are not retained by the body, the need for methods to reduce body burden is uncertain. 

Richelle, M. et al. (2004). Both free and esterified plant sterols reduce cholesterol absorption and the bioavailability of beta-carotene and alpha-tocopherol in normocholesterolemic humans. Am. J. Clin. Nutr. 80(1) 171-177. 

In the stomach, carotenoids are exposed to acid environments. This can lead to carotenoid isomerization, which can change carotenoid antioxidant properties, solubility, and absorption. In humans, (3-carotene absorption is reduced when the pH of the gastric fluids is below 4.5 (Tang and others 1995). Vitamin E consumption seems to reduce carotenoid absorption in animals, presumably because vitamin E and carotenoids compete for absorption (Furr and Clark 1997). Dietary sterols, such as those in sterol-supplemented functional foods, are also known to decrease carotenoid absorption. 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

Wood, R. J., and Zheng, J. J. (1997). High dietary calcium intakes reduce zinc absorption and balance in humans. Am. ]. Clin. Nutr. 65,1803-1809. 

It must have reduced human and environmental absorption. 

There are several ways pectin could reduce serum cholesterol. In studies with human subjects, fecal excretion of bile acids, fatty acids, and total steroids increased when subjects were fed 15-40 g/day of pectin (58, 63, 64). Since pectin usually lowers serum cholesterol only when cholesterol is present in the diet, it seems that pectin might act by reducing cholesterol absorption. Several groups have found that in rats dietary... 

Despite these variables, it appears that the primary attribute of soluble fibers that inhibit cholesterol absorption is the ability to form a viscous matrix when hydrated. Many water-soluble fibers become viscous in the small intestine (Eastwood and Morris, 1992). It is believed that increased viscosity impedes the movement of cholesterol, bile acids, and other lipids and hinders micelle formation, thus reducing cholesterol absorption and promoting cholesterol excretion from the body. Consumption of viscous fibers was shown to increase the thickness of the unstirred water layer in humans (Flourie et al., 1984 Johnson and Gee, 1981) and reduce the amount of cholesterol appearing in the lymph of cannulated rats (Ikeda et al., 1989b Vahouny et al., 1988). Turley et al. (1991, 1994) reported that... 

Competitive mineral-mineral interactions involving chemically similar elements are widespread in nature. Interactions between zinc and iron, and zinc and tin reduce zinc absorption in humans, and pose potential nutritional consequences. Dietary zinc levels may also be of Importance in human copper absorption. Natural foods, alone or in combination, tend to have a balance among minerals, but in the formulation of proprietary vitamin-mineral supplements or Infant foods, there is the potential for creating nutrltionally-signlflcant Imbalances. Little is known about the role of other food components in conditioning these interactions. This question should be a priority for future research. 

Favorable clinical results have been obtained with p.o. doses of 10-20 mg/kg three times a day. Sucralfate can be administered concurrently with an H2 antagonist. Concurrent administration may reduce the absorption of the H2 antagonist by 10% but this has not appeared to affect efficacy in humans (Mullersman et al 1986). Importantly, sucralfate can substantially interfere with the absorption of other drugs, particularly fluoroquinolones, and thus its use concurrently with other medications should be determined on a case-by-case basis. 

PAMPA-biomimetic-Caco-2-comparison Several in vitro assays have been developed to evaluate the Gl absorption of compounds. Our aim was to compare three of these methods (/) the BAMPA method, which offers a HT, noncellular approach to the measurement of passive transport ( ) the traditional Caco-2 cell assay, the use of which as a HT tool is limited by the long cell differentiation time (21 days) and (// ) The BioCoat HTS Caco-2 assay system, which reduces Caco-2 cell differentiation to three days. The transport of known compounds (such as cephalexin, propranolol, or chlorothiazide) was studied at pH 7.4 and 6.5 in BAMPA and both Caco-2 cell models. Permeability data obtained was correlated to known values of human absorption. Best correlations (f= 0.9) were obtained at pH 6.5 for BAMPA and at pH 7.4 for the Caco-2 cells grown for 21 days. The Caco-2 BioCoat HTS Caco-2 assay system does not seem to be adequate for the prediction of absorption. The overall results indicate that BAMPA and the 21 -day Caco-2 system can be complementary for an accurate prediction of human intestinal absorption. 

Whole castor seeds contain oil, phytochemicals, and other potentially purging components that may induce protective vomiting or otherwise reduce Gl absorption of ricin in humans. One must recognize, therefore, that the highly successful clinical outcome of treating accidental or intentional cases of oral poisoning with castor seeds may not accurately predict the human morbidity or mortality associated with consumption of pure or stabilized ricin. 

Kostial K, Kargacin B, Simonovic I. 1987. Reduced radiostrontium absorption in a human subject treated with composite treatment for mixed fission product contamination. Health Phys 52(3) 371-372. 

Recent data indicate that ezetimibe inhibits a specific transport process in jejunal enterocytes, which take up cholesterol from the lumen. The putative transport protein is Niemann-Pick Cl-hke 1 protein (NPCILI). In wild-type mice, ezetimibe inhibits cholesterol absorption by about 70% in NPCILI knockout mice, cholesterol absorption is 86% lower than in wild-type mice, and ezetimibe has no effect on cholesterol absorption. Ezetimibe does not affect intestinal triglyceride absorption. In human subjects, ezetimibe reduced cholesterol absorption by 54%, precipitating a compensatory increase in cholesterol synthesis, which can be inhibited with a cholesterol synthesis inhibitor such as a statin. There is also a substantial reduction of plasma levels of plant sterols (campesterol and sitosterol concentrations are reduced by 48 and 41%, respectively), indicating that ezetimibe also inhibits intestinal absorption of plant sterols. 

Gypsophila saponins have been shown to possess hypocholesterolemic effects in rat [84], The serum cholesterol levels were significantly lower in saponin-fed rats than in control. In another study, Gypsophila saponins were tested in young rats and the results showed that Gypsophila saponins may reduce Fe absorption and have an adverse effect on the Fe status in human and monogastric animals. However, Gypsophila saponins had no effect on Zn absorption [85, 86], Another report showed that the purified saponins from G. capitata were responsible for the hypocholesterolemic effects in rabbits [87]. 

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