Processes of Absorption, Distribution, and Excretion

BY L. F. CHASSEAUD

Much of the organic and inorganic matter ingested by man in his lifetime provides materials for metabolic processes concerned with the production of energy, with the anabolism and catabolism of body tissues and with the general maintenance of the milieu intérieur. Man also ingests, inhales, and absorbs other substances that are not required for these processes but can sometimes seriously upset them. These foreign compounds are generally non-nutrient substances, and include drugs, pesticides, food additives and many other chemicals that affect the environment. They may also be produced within the animal as digestion products of the gut flora.

Metabolic pathways have been evolved which protect the body by converting foreign compounds into more polar derivatives that are more readily excreted. In these metabolic pathways, foreign compounds are chemically transformed by reduction, oxidation, hydrolysis, and conjugation, and undergo one or more of these reactions (see Chapter 5). Foreign compounds seem to be transformed into less toxic or inert products, and for this reason those metabolic pathways have been described as detoxication mechanisms, but sometimes biologically-active metabolites are produced.

Most transformations of foreign compounds are catalysed by enzymes, many of which occur in the liver and to a lesser extent in some other tissues. Those biotransformations depend largely on the structure of the foreign compound, but the effect of the genetic make-up of species, the route of administration, the diet or pretreatment with other substances can regulate metabolism (see Chapter 6).

In the mammalian body, the absorption, distribution, biotransformation, and excretion of foreign compounds are intimately connected processes, themselves subject to many variables. The present chapter discusses the processes of absorption, distribution, and excretion, in some depth, and thereby provides background to the subjects which are developed in the rest of the book, particularly the ones exemplified in Chapter 2.

1 Absorption

Foreign compounds may be taken into the body from the environment by the oral, respiratory, or dermal routes and are circulated in the blood. Drugs, which are generally foreign compounds, are preferably administered orally, intravenously, or intramuscularly.

In a study of its metabolic fate, the foreign compound should be administered by the route by which man, or the species at risk, is likely to be exposed or treated, since the absorption, and therefore the effect of a foreign compound may greatly depend on its route of administration. If rapid metabolism occurs in the liver, many substances are less toxic when administered orally rather than intravenously or intraperitoneally because of the greater concentration first reaching the liver by the hepatic-portal route. Again, if a compound is poorly absorbed, it exerts less effect by oral administration.

Transport Across Membranes. — All foreign compounds absorbed into the body must cross one or more semipermeable membranes, and the effect and distribution of the compound in the body depends on its ability to penetrate these membranes. On both sides of a membrane the effective concentration of the compound is continually decreasing through its localization, bio-transformation, and excretion. Membranes, such as the gastro-intestinal epithelium, the lining of the respiratory tract, and stratum corneum of the skin, delay the passage of the compound into the body, after which membranes enclosing the blood and other body fluids, cell membranes and membranes within cells control the uptake into tissues and sub-cellular components, and ultimately reduce the amount of a compound that reaches its site(s) of action.

These membranes are highly complex, dynamic lipoprotein structures and consist of several layers of cells, such as the skin and the placenta, or of a single layer of cells, such as the intestinal epithelium, or they occur less than one cell in thickness, as in the case of cell membranes. Apart from the thicker, larger biological barriers enclosing intracellular structures, all body membranes are composed of a fundamental structure, that of the cell membrane.

There are several processes by which substances may cross biological membranes (Table 1). Passive transfer processes require that the membrane behaves as an inert solvent–pore boundary through which solutes diffuse by passage through solvent regions or through the pores, or by flowing together with water through the pores. In this case, the solvent is represented by lipoprotein structures of which the aqueous pores comprise a very small part, their size varying with the membrane concerned. These pores should be considered as highly polar regions of the membrane that are solvated with water, not as simple tubes. The equivalent pore radius of the luminal face of rat intestine was shown to be 4 [Angstrom], sufficiently large for molecules such as water or urea to pass through, but too small for mannito1. The equivalent pore size of the membrane of the small intestine may vary, as has been suggested by results obtained with human intestine where the effective pore radius of the jejunum was calculated to be twice that of the ileum which was less than 4 [Angstrom]. However, size is not the only factor that influences the passage of small molecules through these pores. Other factors also restrict the passage of certain small molecules.

Specialized transfer processes exhibit an active nature that shows a high degree of specificity for a particular solute transferred across the membrane, and here structure, conformation, size, and charge are important in determining penetration. Small differences are important in specialized transfer processes, whereas the physical laws apply to the passive transfer of solutes. Specialized transfer processes are largely involved with the transport of nutrients, such as sugars and amino-acids.

Diffusion of Foreign Compounds across Membranes. — Foreign compounds generally cross membranes by passive diffusion down a concentration gradient, which provides the driving force for the movement of these molecules. Some lipid-insoluble foreign compounds of low molecular weight cross membranes by filtration together with water, or by diffusion, through the pores. The driving force for such movement may be provided by electrochemical gradients or by the bulk flow of water. The smaller the compound, the quicker it passes through the pores, but the ionic charge is important for low-molecular-weight ions, for example, certain poorly lipid-soluble organic anions penetrated the erythrocyte membrane much more rapidly...