Xenobiotic absorption

FIGURE 1.11 A scheme of the various absorption routes across the intestinal epithelium and cellular barriers to xenobiotics absorption. A, Transcellular absorption (plain diffusion) B, paracellular absorption C, carrier-mediated transcellular absorption D, facilitated diffusion E, the MDR and P-gp absorption barrier and F, endocytosis. (From Hunter, J. and Hirst, B.H., Adv. Drug Deliv. Rev., 25, 129, 1997. With permission.)... 

The general application of epidemiologic methods to developmental toxicity is described below and followed by a discussion of laboratory studies in rodents and rabbits. The bulk of data available in developmental toxicology are based on these protocols. Since the difference in human and animal response appears to rest in large part on differences in behavior, physiologic parameters, and xenobiotic absorption, distribution, metabolic fate, and elimination, a brief description of transplacental pharmacokinetics is also provided. 

Dermal absorption of agricultural chemicals and animal drugs in food-producing animals must be considered as a potential route from which tissue residues of drugs and chemicals may occur. This has been supported in studies of topical pesticide exposure in cows and sheep. Despite the many advances made in in vitro and in vivo techniques for assessing percutaneous absorption in laboratory animals and man, very little systematic attention has been focussed on food-producing animals. The only exception is the pig since it is an accepted model for human studies. The purpose of this manuscript is to overview the literature on dermal xenobiotic absorption in food-producing animals to illustrate the risk that is present, and to outline how in vitro and in vivo methods could be applied to this problem. 

Xenobiotic absorption utilizing the isolated perfused porcine skin flap (Williams etal., 1990)... 

Regarding the well-described toxic activity of DON against the immune system, alterations of the immune cells could affect the intestinal and brain functions, as recently desciibed. In particular, the intestinal and systemic production of cytokines could participate in the growth retardation, feed refusal and emesis caused by DON on account of the effects on the neuroendocrine system. The consequent inflammation could lead to an increased permeability of the intestinal and blood barriers, thus affecting the xenobiotic absorption. 

The major routes of uptake of xenobiotics by animals and plants are discussed in Chapter 4, Section 4.1. With animals, there is an important distinction between terrestrial species, on the one hand, and aquatic invertebrates and fish on the other. The latter readily absorb many xenobiotics directly from ambient water or sediment across permeable respiratory surfaces (e.g., gills). Some amphibia (e.g., frogs) readily absorb such compounds across permeable skin. By contrast, many aquatic vertebrates, such as whales and seabirds, absorb little by this route. In lung-breathing organisms, direct absorption from water across exposed respiratory membranes is not an important route of uptake. 

Many of the phase 1 enzymes are located in hydrophobic membrane environments. In vertebrates, they are particularly associated with the endoplasmic reticulum of the liver, in keeping with their role in detoxication. Lipophilic xenobiotics are moved to the liver after absorption from the gut, notably in the hepatic portal system of mammals. Once absorbed into hepatocytes, they will diffuse, or be transported, to the hydrophobic endoplasmic reticulum. Within the endoplasmic reticulum, enzymes convert them to more polar metabolites, which tend to diffuse out of the membrane and into the cytosol. Either in the membrane, or more extensively in the cytosol, conjugases convert them into water-soluble conjugates that are ready for excretion. Phase 1 enzymes are located mainly in the endoplasmic reticulum, and phase 2 enzymes mainly in the cytosol. 

Section VI consists of discussions of eleven special topics nutrition, digestion, and absorption vitamins and minerals intracellular traffic and sorting of proteins glycoproteins the extracellular matrix muscle and the cy-toskeleton plasma proteins and immunoglobulins hemostasis and thrombosis red and white blood cells the metabolism of xenobiotics and the Human Genome Project. 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Garrigues, T. M. Perez-Varona, A. T. Climent, E. Bermejo, M. V. Martin-Villodre, A. Pla-Delfina, J. M., Gastric absorption of acidic xenobiotics in the rat Biophysical interpretation of an apparently atypical behaviour, hit. J. Pharm. 64, 127-138 (1990). 

The intestinal wall is optimized to absorb fluids and nutrients while keeping away different xenobiotics. Which factors, from a theoretical point of view, are the most influential in intestinal absorption ... 

The process by which a xenobiotic and its metabolites are transferred from the site of absorption to the blood circulation. 

The phenomenon whereby xenobiotics may he extracted or metabolized following enteral absorption before reaching the systemic circulation. 

PXR CAR FXR LXR AhR 3A4 and others 2B, 2C, 3A4 7A 7A 1A1, 1A2, 1A6, 1B1, 2S1 Xenobiotic metabolism regulation, antioxidant Xenobiotic metabolism regulation Bile add metabolism and transport Reverse cholesterol transport and absorption Reproduction and development regulation... 

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