Metabolism of drugs by the kidney

The kidneys have many clearly defined physiologic functions. Although their role as an excretory organ for drugs and chemicals and their polar metabolites is well described, their involvement in the biotransformation of xenobiotics is relatively poorly understood. It is accurate to state that our present understanding of the metabolic processes of drugs is based largely on studies carried out in the liver. Only recently have detailed investigations into drug metabolism in the kidney been carried out. These studies have shown that the kidney is meta-bolically very active in effecting the biotransformation of a variety of chemicals and drugs and, in some cases, surpasses the liver. It is important to understand the role of the kidney in drug and chemical biotransformation for a variety of reasons. Because the kidney receives a substantial portion of the cardiac output, it is reasonable to expect that it may make a significant contribution to the total metabolic alteration of drugs in the body. Furthermore, it is now known that the toxic effects of many drugs and chemicals are attributable to their metabolic conversion to reactive electrophilic intermediates, which, on reaction with cellular nucleophiles, lead to a variety of deleterious effects. Perhaps most important is the appreciation that this interaction between reactive intermediates and critical cellular macromolecules is intimately involved in mutagenic and carcinogenic changes. In addition, necrotic changes may also be associated with cellular alkylation. Thus, a complete perspective on the role of the kidney in pharmacologic and toxicologic processes is dependent on a thorough understanding of the drug and chemical metabolic capabilities of this organ. The biotransformation of organic compounds can be conveniently divided into oxidative, reductive, hydrolytic, and synthetic or conjugation reactions. The first three reactions are based on the type of chemical change produced. Synthetic or conjugation reactions usually involve the enzyme-catalyzed combination of a chemical or a metabolite and a carbohydrate or an amino acid, and they yield highly polar, readily excretable metabolites. Furthermore, multiple metabolic alterations are very common. Williams, in his classic book, Detoxication Mechanisms, suggests that the metabolism of many xenobiotics occurs in two steps [1]. The first, termed "phase I reactions," includes oxidative, reductive, and hydrolytic reactions; the second, termed "phase II reactions," consists of conjugative reactions and includes, for example, glucuronide, sulfate, and hippuric acid formation. It should be noted that although the metabolites produced in phase I reactions are frequently less toxic or less active pharmacologically than the parent compound is, abundant examples can be cited where the metabolites are more toxic and more active pharmacologically. By the same token, although the conjugates produced in phase II reactions are usually very polar and less toxic, notable exceptions exist; for example, the sulfate conjugate of N-hydroxyacetyl-aminofluorene is thought to be the proximate carcinogen in the case of this compound [5].