FACTORS AFFECTING DRUG METABOLISM

Abstract

The biological fate of a drug depends on a host of factors, including those which determine its volume of distribution, its excretion into air, bile, and urine, and its metabolism by various enzyme systems in the body. A number of foreign compounds closely resemble normal body substances and thus can interact with rather specific transport systems, carrier proteins, and enzymes. Analogues of purines, pyrimidines, fatty acids, steroids, amino acids, and biogenic amines belong to this group. In general, however, foreign compounds have no endogenous counterpart and are metabolized by nonspecific enzymes and transported by either passive diffusion or nonspecific transport systems. I t is now known that most foreign compounds are metabolized along a diversity of chemical pathways leading to a wide variety of urinary metabolites. Several years ago, Dr. R. T. Williams' pointed out that foreign compounds are usually converted into metabolites of ever increasing polarity until finally they can be readily excreted by the kidney. This process is usually carried out in two general phases (TABLE 1): (1) Polar groups are introduced into nonpolar compounds by oxidation, reduction, and hydrolysis reactions, or alkyl groups are removed to uncover potential polar groups; (2) the polar group is conjugated with glucuronate, sulfate, glycine, glutamine, acetate, or methyl groups. The metabolites formed by these various reactions have different volumes of distribution and are excreted by the kidney at different rates. Thus, the relative amounts of metabolites in urine provide only indirect and frequently fallacious estimates of their concentrations in body tissues and blood plasma. For this reason, many studies of drug metabolism include the isolation of metabolites from tissues. Even in these studies, however, the relative importance and location of the enzymes operative in drug metabolism in different tissues are obscure because the metabolites may be located in tissues other than those in which they are formed. Studies in uitro have revealed that liver is the main site for the metabolism of foreign compounds by nonspecific enzymes, although metabolism may also occur to varying extents in other tissues and bacterial flora of the gastrointestinal tract. During the past several years, it has become increasingly evident that most of the oxidative reactions are catalyzed by enzyme systems in liver endoplasmic reticulum, which is disrupted by homogenization to form microsomes. Indeed, the diversity of the reactions catalyzed by these enzymes is virtually unique in biochemistry (TABLE 2).