Principles of Drug Metabolism

PRINCIPLES OF DRUG METABOLISM In pharmacology, one speaks of pharmacodynamic effects to indicate what a drug does to the body, and pharmacokinetic effects to indi- BERNARD TESTA Department of Pharmacy, University Hospital cate what the body does to a drug, two aspects Centre, CH-1011 Lausanne, Switzerland of the behavior of drugs that are strongly inter- dependent. Pharmacokinetic effects will ob- viously have a decisive influence on the 1. INTRODUCTION intensity and duration of pharmacodynamic effects, while metabolism will generate new Xenobiotic metabolism, which includes drug chemical entities (metabolites) that may metabolism, has become a major pharmacolo- have distinct pharmacodynamic properties of gical science with particular relevance to biol- their own. Conversely, by its own pharmaco- ogy, therapeutics and toxicology. Drug meta- dynamic effects, a compound may affect the bolism is also of great importance in medicinal state of the organism (e.g., hemodynamic chemistry because it influences in qualitative, changes, enzyme activities, etc.) and hence the quantitative, and kinetic terms the deactiva- organism’s capacity to handle xenobiotics. tion, activation, detoxification, and toxifica- Only a systemic approach can help one appreci- tion of the vast majority of drugs. As a result, ate the global nature of this interdependence. medicinal chemists engaged in drug discovery and development should be able to integrate metabolic considerations into drug design. To 1.2. Types of Metabolic Reactions Affecting do so, however, requires a fair or even good Xenobiotics knowledge of xenobiotic metabolism. A first discrimination to be made among me- This chapter, which is written by a medic- tabolic reactions is based on the nature of the inal chemist for medicinal chemists, aims at catalyst. Reactions of xenobiotic metabolism, offering knowledge and understanding rather like other biochemical reactions, are than encyclopedic information. Readers want- catalyzed by enzymes. However, while the vast majority ing to go further in the study of xenobiotic of reactions of xenobiotic metabolism are in- metabolism may consult various classical or deed enzymatic ones, some recent books [1–15], broad reviews, and book nonenzymatic reactions are also well documented. This is due chapters [16–27]. to the fact that a variety of xenobiotics have been found to be labile enough to react none- 1.1. Deﬁnitions and Concepts nzymatically under biological conditions of Drugs are but one category among the many pH and temperature [28]. But there is more. xenobiotics (Table 1) that enter the body but In a normal enzymatic reaction, metabolic have no nutritional or physiological value [14]. intermediates exist en route to the product The study of the disposition—or fate—of xe- (s) and do not leave the catalytic site. However, nobiotics in living systems includes the con- many exceptions to this rule are known, with sideration of their absorption into the organ- the metabolic intermediate leaving the active ism, how and where they are distributed and site and reacting with water, with an endo- stored, the chemical and biochemical trans- genous molecule or macromolecule, or with a formations they may undergo, and how and xenobiotic. Such reactions are also of a none- by which route(s) they are finally excreted nzymatic nature but are better designated as and returned to the environment. As for postenzymatic reactions. “metabolism,” this word has acquired two The metabolism of drugs and other xeno- meanings, being synonymous with disposition biotics is often a biphasic process in which the (i.e., the sum of the processes affecting the fate compound may first undergo a functionaliza- of a chemical substance in the body), and with tion reaction (phase I reaction) of oxidation, biotransformation as understood in this reduction, or hydrolysis. This introduces or chapter. unveils a functional group such as a hydroxy 405 Burger’s Medicinal Chemistry, Drug Discovery, and Development, Seventh Edition, edited by Donald J. Abraham and David P. Rotella Copyright Ó 2010 John Wiley & Sons, Inc. 406 PRINCIPLES OF DRUG METABOLISM Table 1. Major Categories of Xenobiotics 1.3. Speciﬁcities and Selectivities (Modified from Ref. [14]) in Xenobiotic Metabolism . Drugs The words “selectivity” and “specificity” may . Food constituents devoid of physiological roles not have identical meanings in chemistry and . Food additives (preservatives, coloring and fla- biochemistry. In this chapter, the specificity of voring agents, antioxidants, etc.) . Chemicals of leisure, pleasure, or abuse (ethanol, an enzyme is taken to mean an ensemble of coffee and tobacco constituents, hallucinogens, properties, the description of which makes it doping agents, etc.) possible to specify the enzyme’s behavior. In . Agrochemicals (fertilizers, insecticides, herbicides, contrast, the term selectivity is applied to etc.) metabolic processes, indicating that a given . Industrial and technical chemicals (solvents, dyes, metabolic reaction or pathway is able to select monomers, polymers, etc.) some substrates or products from a larger set. Pollutants of natural origin (radon, sulfur dioxide, In other words, the selectivity of a metabolic hydrocarbons, etc.) reaction is the detectable expression of the . Pollutants produced by microbial contamination specificity of an enzyme. Such definitions may (e.g., aflatoxins) . Pollutants produced by physical or chemical not be universally accepted, but they have the transformation of natural compounds (polycyclic merit of clarity. aromatic hydrocarbons by burning, Maillard re- What, then, are the various types of selec- action products by heating, etc.) tivities (or specificities) encountered in xenobiotic metabolism? What characterizes an enzyme from a catalytic viewpoint is first its chemospecificity, that is, its specificity in terms of the type(s) of reaction it catalyzes. When two or more substrates are metabolized or amino group suitable for coupling with an at different rates by a single enzyme under endogenous molecule or moiety in a second identical conditions, substrate selectivity is metabolic step known as a conjugation reac- observed. In such a definition, the nature of tion (phase II reaction) [19,24]. In a number of the product(s) and their isomeric relationship cases, phase I metabolites may be excreted are not considered. Substrate selectivity is prior to conjugation, while many xenobiotics distinct from product selectivity, which is ob- can be directly conjugated. Furthermore, re- served when two or more metabolites are actions of functionalization may follow some formed at different rates by a single enzyme reactions of conjugation, for example, some from a single substrate. Thus, substrate-se- conjugates are hydrolyzed and/or oxidized lective reactions discriminate between differ- prior to their excretion. ent compounds, while product-selective reac- Xenobiotic biotransformation thus pro- tions discriminate between different groups or duces two types of metabolites, namely func- positions in a given compound. tionalization products and conjugates. But The substrates being metabolized at differ- with the growth of knowledge, biochemists ent rates may share various types of relation- and pharmacologists have progressively come ships. They may be chemically dissimilar or to recognize the existence of a third class of similar (e.g., analogs), in which case the term metabolites, namely xenobiotic–macromole- of substrate selectivity is used in a narrow cule adducts, also called macromolecular con- sense. Alternatively, the substrates may be jugates. Such peculiar metabolites are formed isomers such as positional isomers (regioi- when a xenobiotic binds covalently to a biolo- somers) or stereoisomers, resulting in sub- gical macromolecule, usually following meta- strate regioselectivity or substrate stereose- bolic activation (i.e., postenzymatically). Both lectivity. Substrate enantioselectivity is a par- functionalization products and conjugates ticular case of the latter (see Section 4.2.1). have been found to bind covalently to biologi- Products formed at different rates in pro- cal macromolecules, the reaction often being duct-selective reactions may also share var- toxicologically relevant. ious types of relationships. Thus, they may be INTRODUCTION 407 analogs, regioisomers, or stereoisomers, re- one of toxification. Such a metabolite may act sulting in product selectivity (narrow sense), or react in a number of ways to elicit a variety product regioselectivity, or product stereose- of toxic responses at different biological levels. lectivity (e.g., product enantioselectivity). However, it is essential to stress that the Note that the product selectivity displayed by occurrence of a reaction of toxification (i.e., two distinct substrates in a given metabolic toxicity at the molecular level) does not neces- reaction may be different, in other words the sarily imply toxicity at the levels of organs and product selectivity may be substrate-selective. organisms, as discussed later in this chapter. The term substrate–product selectivity can be used to describe such complex cases, 1.5. Setting the Scene which are conceivable for any type of selectivity but have been reported mainly for In drug research and development, metabo- stereoselectivity. lism is of pivotal importance due to the inter- connectedness between pharmacokinetic and 1.4. Pharmacodynamic Consequences pharmacodynamic processes [14]. In vitro me- of Xenobiotic Metabolism

Load more