O Reductive Reactions

Reductive processes play an important role in the metabolism of many compounds containing carbonyl, nitro, and azo groups. Bioreduction of carbonyl compounds generates alcohol derivatives,116,285 whereas nitro and azo reductions lead to amino derivatives.286 The hydroxyl and amino moieties of the metabolites are much more susceptible to conjugation than the functional groups of the parent compounds. Hence, reductive processes, as such, facilitate drug elimination.

Amine Ketone MetabolismAldehyde Reduction AmphetamineAddition Reaction Amphetamine

Reductive pathways that are encountered less frequently in drug metabolism include reduction of N-oxides to their corresponding tertiary amines and reduction of sulfoxides to sulfides. Reductive cleavage of disulfide linkages and reduction of carbon-carbon double bonds also occur, but constitute only minor pathways in drug metabolism.

Reduction of Aldehyde and Ketone Carbonyls

The carbonyl moiety, particularly the ketone group, is encountered frequently in many drugs. In addition, metabolites containing ketone and aldehyde functionalities often arise from oxidative deamination of xenobiotics (e.g., propranolol, chlorpheniramine, amphetamine). Because of their ease of oxidation, aldehydes are metabolized mainly to carboxylic acids. Occasionally, aldehydes are reduced to primary alcohols. Ketones, however, are generally resistant to oxidation and are reduced mainly to secondary alcohols. Alcohol metabolites arising from reduction of carbonyl compounds generally undergo further conjugation (e.g., glucuronidation).

Diverse soluble enzymes, called aldo-keto reductases, carry out bioreduction of aldehydes and ketones.116,287 They are found in the liver and other tissues (e.g., kidney). As a general class, these soluble enzymes have similar physio-chemical properties and broad substrate specificities and require NADPH as a cofactor. Oxidoreductase enzymes that carry out both oxidation and reduction reactions also can reduce aldehydes and ketones.287 For example, the important liver alcohol dehydrogenase is an NAD+-dependent-oxidoreductase that oxidizes ethanol and other aliphatic alcohols to aldehydes and ketones. In the presence of NADH or NADPH, however, the same enzyme system can reduce carbonyl derivatives to their corresponding alcohols.116

Few aldehydes undergo bioreduction because of the relative ease of oxidation of aldehydes to carboxylic acids. However, one frequently cited example of a parent aldehyde drug undergoing extensive enzymatic reduction is the sedative-hypnotic chloral hydrate. Bioreduction of this hydrated aldehyde yields trichloroethanol as the major metabolite in humans.288 Interestingly, this alcohol metabolite is pharmacologically active. Further glucuronidation of the alcohol leads to an inactive conjugated product that is readily excreted in the urine.

Aldehyde metabolites resulting from oxidative deamina-tion of drugs also undergo reduction to a minor extent. For example, in humans the ^-adrenergic blocker propranolol is converted to an intermediate aldehyde by N-dealkylation and oxidative deamination. Although the aldehyde is oxidized primarily to the corresponding carboxylic acid (naphthoxylactic acid), a small fraction is also reduced to the alcohol derivative (propranolol glycol).289

Two major polar urinary metabolites of the histamine H1-antagonist chlorpheniramine have been identified in dogs as the alcohol and carboxylic acid products (conjugated) derived, respectively, by reduction and oxidation of an aldehyde metabolite. The aldehyde precursor arises from bis-N-demethylation and oxidative deamination of chlorpheniramine.290

Bioreduction of ketones often leads to the creation of an asymmetric center and, thereby, two possible stereoisomeric alcohols.116,291 For example, reduction of acetophenone by a soluble rabbit kidney reductase leads to the enantiomeric alcohols (S)( —)- and (R)(+)-methylphenylcarbinol, with the (S)( —)-isomer predominating (3:1 ratio).292 The preferential formation of one stereoisomer over the other is termed product stereoselectivity in drug metabolism.291 Mechanistically, ketone reduction involves a "hydride" transfer from the reduced nicotinamide moiety of the cofactor NADPH or NADH to the carbonyl carbon atom of the ketone. It is generally agreed that this step proceeds with considerable stereoselectivity.116,291 Consequently, it is not surprising to find many reports of xenobiotic ketones that are reduced preferentially to a predominant stereoisomer. Often, ketone reduction yields alcohol metabolites that are pharmacologically active.

Although many ketone-containing drugs undergo significant reduction, only a few selected examples are presented in detail here. The xenobiotics that are not discussed in the text have been structurally tabulated in Figure 3.10. The keto group undergoing reduction is designated with an arrow.

Ketones lacking asymmetric centers in their molecules, such as acetophenone or the oral hypoglycemic acetohex-amide, usually give rise to predominantly one enantiomer on reduction. In humans, acetohexamide is metabolized rapidly in the liver to give principally (S)( —)-hydroxyhexam-ide.293,294 This metabolite is as active a hypoglycemic agent as its parent compound and is eliminated through the kidneys.295 Acetohexamide usually is not recommended in diabetic patients with renal failure, because of the possible accumulation of its active metabolite, hydroxyhexamide.

When chiral ketones are reduced, they yield two possible diastereomeric or epimeric alcohols. For example, the (R)(+) enantiomer of the oral anticoagulant warfarin undergoes extensive reduction of its side chain keto group to generate the (R,S)(+) alcohol as the major plasma metabolite in humans.56,296 Small amounts of the (R,R)(+) diastereomer are also formed. In contrast, the (S)(—) enantiomer undergoes little ketone reduction and is primarily 7-hydroxylated (i.e., aromatic hydroxylation) in humans.

Reduction of the 6-keto functionality in the narcotic antagonist naltrexone can lead to either the epimeric 6a-or 6^-hydroxy metabolites, depending on the animal species.297,298 In humans and rabbits, bioreduction of naltrexone is highly stereoselective and generates only 6j8-naltrexol, whereas in chickens, reduction yields only 6a-

Examples Narcotic AntagonistOpium Zusammmen Setzung
Figure 3.10 • Additional examples of xenobiotics that undergo extensive ketone reduction, not covered in the text. Arrow indicates the keto group undergoing reduction.
Phonics Versus

naltrexol.297-299 In monkeys and guinea pigs, however, both epimeric alcohols are formed (predominantly 6j8-naltrexol).300,301 Apparently, in the latter two species, reduction of naltrexone to the epimeric 6a- and 6^-alcohols is carried out by two distinctly different reductases found in the liver.299-301

Reduction of oxisuran appears not to be an important pathway by which the parent drug mediates its immunosuppressive effects. Studies indicate that oxisuran has its greatest immunosuppressive effects in those species that form alcohols as their major metabolic products (e.g., human, rat).302-306 In species in which reduction is a minor pathway (e.g., dog), oxisuran shows little immunosuppressive activ ity.

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