Phase I Reactions: Hydrolysis, Reduction, and Oxidation

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The page below is a sample from the LabCE course Drug Metabolism. Access the complete course and earn ASCLS P.A.C.E.-approved continuing education credits by subscribing online.

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Phase I Reactions: Hydrolysis, Reduction, and Oxidation

The enzyme-catalyzed reactions of Phase I metabolism add oxygen, hydrogen, water, or amino acids to lipophilic drug molecules with the aim of exposing or introducing a polar function group (such as a hydroxyl (-OH), amino (-NH2), sulfhydryl (-SH), or carboxyl (-COOH) group). In this way, they change the drug into a compound which has increased water solubility. These reactions include hydrolysis, reduction, and oxidation.
  • In a reaction with water, a bond in the compound is broken, resulting in two compounds. At the same time the water molecule splits in two, with a hydrogen transferring to one of the compounds and a hydroxide to the other compound.
    • R-COO-R' + H2O R-COOH + R'-OH
    • R-CO-NH-R' + H2O R-COOH + R'-NH2
  • The conversion of cocaine to benzoylecognine and ecognine methyl ester are examples of hydrolysis reactions.
  • Some enzymes that perform hydrolysis reactions include esterases, peptidases, and amidases.
  • Reactions resulting in the addition of hydrogen and/or the removal of oxygen:
    • R-OH R-H (de-hydroxylation)
    • R-C=O R-C-OH (hydrogenation)
    • R-COOH R-C=O (decarboxylation)
    • R-NO2 R-NH2 (amination)
    • R-C-H R-CH3 (methylation)
  • An example of a reduction reaction is the inactivation of warfarin by the transformation of a ketone group to a hydroxyl group (hydrogenation).
  • Enzymes involved in reduction reactions are called reductases.
  • Reactions resulting in the addition of oxygen and/or the removal of hydrogen:
    • R-H R-OH (hydroxylation): Conversion of a hydrogen to a hydroxyl group.
    • R-C-OH R-C=O (dehydrogenation): Conversion of a hydroxyl group to a carbonyl group.
    • R-C=O R-COOH (carboxylation): Conversion of a carbonyl group to a carboxyl group.
    • R-C-NH2R-C=O (deamination): Conversion of an amino group to a carbonyl group.
    • R-CH3R-H (demethylation): Conversion of a methyl group to a hydrogen.
  • An example of an oxidation reaction is the hydroxylation of amphetamine to 4-hydroxyamphetamine and norephedrine. Another example is hydroxylation of delta-9-THC to 11-OH-delta-9-THC.
  • The enzymes of oxidation include mixed-function oxidases, monoxygenases, and cytochrome P450 enzymes.