Drug metabolism reactions have been divided into two categories: phase I (functionalization) and phase II (conjugation) reactions.1'7 Phase I, or functionalization reactions, include oxidative, reductive, and hydrolytic biotransformations (Table 3.1).8 The purpose of these reactions is to introduce a functional polar group(s) (e.g., OH, COOH, NH2, SH) into the xenobiotic molecule to produce a more water-soluble compound. This can be achieved by direct introduction of the functional group (e.g., aromatic and aliphatic hydroxylation) or by modifying or "unmasking" existing functionalities (e.g., reduction of ketones and aldehydes to alcohols; oxidation of alcohols to acids; hydrolysis of ester and amides to yield COOH, NH2, and OH groups; reduction of azo and nitro compounds to give NH2 moieties; oxidative N-, O-, and S-dealkylation to give NH2, OH, and SH groups). Although phase I reactions may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group or "handle" on the molecule that can undergo subsequent phase II reactions.
The purpose of phase II reactions is to attach small, polar, and ionizable endogenous compounds such as gluc-uronic acid, sulfate, glycine, and other amino acids to the functional handles of phase I metabolites or parent compounds that already have suitable existing functional groups to form water-soluble conjugated products. Conjugated metabolites are readily excreted in the urine
TABLE 3.1 General Summary of Phase I and Phase II Metabolic Pathways
Phase I or Functionalization Reactions
Oxidation at benzylic, allylic carbon atoms, and carbon atoms a to carbonyl and imines Oxidation at aliphatic and alicyclic carbon atoms Oxidation involving carbon-heteroatom systems: Carbon-nitrogen systems (aliphatic and aromatic amines; includes W-dealkylation, oxidative deamination, W-oxide formation, W-hydroxylation) Carbon-oxygen systems (O-dealkylation) Carbon-sulfur systems (S-dealkylation, S-oxidation, and desulfuration) Oxidation of alcohols and aldehydes Other miscellaneous oxidative reactions
Reduction of aldehydes and ketones Reduction of nitro and azo compounds Miscellaneous reductive reactions
Hydrolytic Reactions Hydrolysis of esters and amides
Hydration of epoxides and arene oxides by epoxide hydrase
Phase II or Conjugation Reactions
Conjugation with glycine, glutamine, and other amino acids
Glutathione or mercapturic acid conjugation
Methylation and are generally devoid of pharmacological activity and toxicity in humans. Other phase II pathways, such as methylation and acetylation, terminate or attenuate biological activity, whereas glutathione (GSH) conjugation protects the body against chemically reactive compounds or metabolites. Thus, phase I and phase II reactions comple ment one another in detoxifying, and facilitating the elimination of, drugs and xenobiotics.
To illustrate, consider the principal psychoactive constituent of marijuana, A9-tetrahydrocannabinol (A9-THC, also known as A1-THC, depending on the numbering system being used). This lipophilic molecule (octanol/water partition coefficient —6,000)9 undergoes allylic hydroxylation to give 11-hydroxy-A9-THC in humans.10,11 More polar than its parent compound, the 11-hydroxy metabolite is further oxidized to the corresponding carboxylic acid derivative A9-THC-11-oic acid, which is ionized (pKa COOH —5) at physiological pH. Subsequent conjugation of this metabolite (either at the COOH or phenolic OH) with glucuronic acid leads to water-soluble products that are readily eliminated in the urine.12
In the series of biotransformations, the parent A9-THC molecule is made increasingly polar, ionizable, and hy-drophilic. The attachment of the glucuronyl moiety (with its ionized carboxylate group and three polar hydroxyl groups; see structure) to the A9-THC metabolites notably favors partitioning of the conjugated metabolites into an aqueous medium. This is an important point in using urinalysis to identify illegal drugs.
The purpose of this chapter is to provide students with a broad overview of drug metabolism. Various phase I and phase II biotransformation pathways (see Table 3.1) are outlined, and representative drug examples for each pathway are presented. Drug metabolism examples in humans are emphasized, although discussion of metabolism in other mammalian systems is necessary. The central role of the cytochrome P450 (CYP) monooxygenase system in oxidative drug biotransformation is elaborated. Discussion of other enzyme systems involved in phase I and phase II reactions is presented in their respective sections. In addition to stereochemical factors that may affect drug metabolism, biological factors such as age, sex, heredity, disease state, and species variation are considered. The effects of enzyme induction and inhibition on drug metabolism and a section on pharmacologically active metabolites are included.
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