5.5: Phase I Reactions: Reductive Reactions

Phase I biotransformation reductive reactions are chemical processes that modify drugs by introducing or revealing polar functional groups via reduction. Enzymes called reductases catalyze these reactions, playing a pivotal role in drug metabolism by transforming lipophilic drugs into more polar, water-soluble metabolites for easy excretion. An essential type of reductive reaction is the carbonyl group reduction, where aldehydes and ketones are reduced to alcohols. An example is the enzyme-catalyzed conversion of acetaldehyde to ethanol by aldehyde dehydrogenase or the transformation of acetophenone to phenylethanol, signifying the reduction of ketones.

Reductive reactions also target alcohols and carbon-carbon double bonds. The enzyme alcohol dehydrogenase oxidizes alcohols to aldehydes or ketones, as exemplified by the conversion of retinol to retinaldehyde. Carbon-carbon double bonds can be diminished to single bonds through enzymes like cytochrome P450 reductase, as seen in the reduction of fumarate to succinate.

Reduction reactions extend to N-compounds such as nitro, azo, and N-oxide. Nitroreductases, for instance, reduce nitro groups to amino groups, as demonstrated by the conversion of nitrofurantoin to its amine form. Miscellaneous reductive reactions cover the reduction of diverse functional groups. For example, azoreductases reduce azo compounds to primary amines, as in the transformation of sulfasalazine to mesalamine and sulfapyridine.

Reductive reactions in phase I biotransformation contribute significantly to drug detoxification and are instrumental in drug elimination from the body.

Reductive reactions introduce electrons to drug molecules, affecting polar functional groups like hydroxy and amino, allowing subsequent biotransformation or conjugation.

Carbonyl group reductions transform aliphatic carbonyl compounds and aromatic and alicyclic ketones to alcohols. For example, naltrexone transforms into its isomorphine derivative.

C=C reductions, as seen in steroids like norethindrone, convert double bonds into single bonds. Alcohols undergo dehydration to alkenes before reduction, as exemplified by the metabolites of the antispasmodic drug bencyclane.

N-compound reductions transform nitro, azo, and N-oxide groups to their reduced forms. For instance, nitro reduction in nitrazepam proceeds via nitroso and hydroxylamine intermediates to yield an amine.

Prontosil, an azo drug, undergoes reduction to active sulfanilamide, while imipramine N-oxide is converted to imipramine.

Miscellaneous reductive reactions encompass various reduction processes in drug metabolism.

The anesthetic halothane undergoes reductive dehalogenation, and is converted to trifluoroacetic acid or its derivatives.