Xenobiotic lipid solubility

The blood-brain barrier (BBB) forms a physiological barrier between the central nervous system and the blood circulation. It consists of glial cells and a special species of endothelial cells, which form tight junctions between each other thereby inhibiting paracellular transport. In addition, the endothelial cells of the BBB express a variety of ABC-transporters to protect the brain tissue against toxic metabolites and xenobiotics. The BBB is permeable to water, glucose, sodium chloride and non-ionised lipid-soluble molecules but large molecules such as peptides as well as many polar substances do not readily permeate the battier. 

Lipid-soluble xenobiotics are commonly biotra ns formed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated ... 

The formation of polar metabolites from nonpolar materials may actually facilitate monitoring programs—in many cases the polar chemicals are highly concentrated in certain body fluids such as bile and urine. On the other hand, materials such as certain cyclodienes and polychlorinated biphenyls, which are very lipid soluble and resistant to metabolism, may accumulate and these chemicals may persist in the environment and may be transferred via the food chain to man. There is also interest in these biotransformation processes in lower organisms since the simplicity of these systems may lead to a better understanding of the phylogenetic development of xenobiotic metabolism. 

In the present compilation of the distribution and pharmacokinetic data of a dozen xenobiotics studied in the dogfish shark, this species yielded excellent data consistent with what we know from similar studies on terrestrial mammals. The data from the shark occasionaly provided information not available in other animals. Major transport parameters in this fish were shown to be similar to those found in mammals. This aquatic organism handles lipid-soluble pollutants by sequestering them in its fatty liver. Together with a previous summary (23) we have now studied about three dozen xenobiotics in this species. Because of its ease of handling, low cost, abundance, predictive value of transport mechanisms, and well-developed pharmacokinetics, the dogfish shark is an ideal fish species to use as a model to study aquatic pollutants. 

An alternative process that can lead to the termination or alteration of biologic activity is metabolism. In general, lipophilic xenobiotics are transformed to more polar and hence more readily excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite dramatic. For example, lipophilic barbiturates such as thiopental and pentobarbital would have extremely long half-lives if it were not for their metabolic conversion to more water-soluble compounds. 

The permeability of the skin to a toxic substance is a function of both the substance and the skin. The permeability of the skin varies with both the location and the species that penetrates it. In order to penetrate the skin significantly, a substance must be a liquid or gas or significantly soluble in water or organic solvents. In general, nonpolar, lipid-soluble substances traverse skin more readily than do ionic species. Substances that penetrate skin easily include lipid-soluble endogenous substances (hormones, vitamins D and K) and a number of xenobiotic compounds. Common examples of these are phenol, nicotine, and strychnine. Some military poisons, such as the nerve gas sarin (see Section 18.8), permeate the skin very readily, which greatly adds to then-hazards. In addition to the rate of transport through the skin, an additional factor that influences toxicity via the percutaneous route is the blood flow at the site of exposure. 

Metabolism is a complex and fascinating process. It is extremely useful in getting rid of bodily toxicants. Apart from all of the toxicants in the man-made environment around us, even animal and plant food contains many chemicals that have no nutritional value but do have potential toxicity. If these chemicals are sufficiently lipid-soluble, they will reach the blood, and they will not be readily excreted unless they are converted to more water-soluble metabolites. This may be the reason why all animals have a wide variety of xenobiotic-metabolizing enzymes that convert a wide range of chemical structures to water-soluble metabolites that can be excreted in urine (Mulder, 2006). 

In general, the placenta is a poor barrier to xenobiotics and allows for bidirectional transfer of most substances. The majority of molecules cross the placenta via diffusion along a concentration gradient, the rate of which is a product of the agent s size, charge, lipid solubility, and affinity for other biomolecules. 

Such lipid-soluble, non-excretable substances — if subject to glomerular filtration — are almost completely reabsorbed from the primary urine by renal tubules, with the result that they are hardly ever excreted via the kidney. This might involve the danger of accumulations of lipophilic xenobiotics in the body, especially in fatty tissue. Therefore hydrophilization of these substances (with... 

Dioxins are highly lipid soluble and are efficiently absorbed by most routes of exposure although absorption will vary quantitatively depending on the route. Because dioxins are poor substrates for the enzymes typically involved with biotransformation of xenobiotics, they are very poorly metabolized. Dioxins tend to exhibit high concentrations in the liver and tend to accumulate in fatty tissue. Because of their high lipid solubility and poor metabolism, excretion of dioxins is extremely slow. The elimination half-hfe in humans is 10 years. 

As the induction of hepatic microsomal oxidative activity by a lipid-soluble drug (e.g. phenobarbitone) or xenobiotic could decrease the duration of action of therapeutic agents that are mainly eliminated by microsomal oxidation, the effect of induction would be considered a form of biochemical antagonism. Drug-induced inhibition of microsomal oxidative activity, without adjustment of dosage of a concomitantly administered therapeutic agent that undergoes extensive hepatic metabolism, could lead to toxicity. Cimetidine, ketoconazole and chloramphenicol inhibit hepatic microsomal enzyme activity. 

Glycerol trioleate has been used in an attempt to simulate lipid membranes and to take into account some of the solvent associations plausibly occurring in biota an impressive direct correlation was observed between log Phv (Phv is the partition coefficient between glycerol trioleate and water) and BCF values in rainbow trout expressed on a lipid basis, and these results were used to support the view that the bioconcentration of nonpolar hydrophobic xenobiotics is significantly determined by their lipid solubility (Chiou 1985). This conclusion is further supported by the results of an extensive examination of a series of highly hydrophobic compounds which do not demonstrate a high potential for bioconcentration (Chessells et al. 1992). 

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