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-NH2⇒R-C=O (deamination): Conversion of an amino group to a carbonyl group.
- R-CH3⇒ R-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.