Chapter 32. Mechanistic Aspects of Xenobiotic Metabolism as Related to Drug Design

Abstract

Metabolic transformations of drugs and xenobiotics are catalyzed largely, though certainly not exclusively, by a group of detoxication enzymes. Examples of such enzymes include the cytochromes P-450 and lavin, containing monooxygenases, reductases and dehydrogenases, hydrolases, including esterases and epoxide hydrolase, and a variety of transferases, such as glutathione S-transferase, UDP-glucuronyltransferase, and sulfotransferases. The participation of enzymes other than detoxication enzymes in drug metabolism is also common, because many therapeutic agents are structural mimics of endogenous compounds and are, therefore, substrates for specific enzymes normally associated with “natural” substances. Species to species differences in drug metabolism and xenobiotic metabolizing enzymes are well documented. Genetic polymorphism of, for example, human detoxication enzymes can give rise to tremendous differences in metabolism. Kinetic analysis is the single most useful tool for establishing the catalytic behavior of detoxication enzymes. For multiple substrate reactions, the order of addition of substrates and release of products can give a vague notion of the mutual orientation of the substrates or products in the active site. Conventional initial velocity steady-state kinetic measurements, along with substrate, product, and dead-end inhibition can be used to determine the kinetic mechanism. The study of oxidative transformations dominates the field of drug and xenobiotic metabolism. The central role and versatile catalytic nature of the cytochromes P-450 continues to attract enormous interest. Interesting and informative observations on the stereochemistry of cytochrome P-450-catalyzed oxidations continue to be made with enzymes from species other than man. Knowledge of metabolism has contributed significantly to the discovery of new drugs, to the design of drugs with altered metabolic and pharmacokinetic profiles, and particularly to the development of prodrugs. This knowledge includes active metabolic studies and alteration–metabolic profiles. The formation of an active species from a precursor may involve a number of enzymic transformations. Though such conversion is not particularly efficient and extrapolation of results to humans is difficult, it may prove to be an informative example of the complexities that can be encountered in the metabolic activation of a prodrug.