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Chapter: Biopharmaceutics and Pharmacokinetics : Biotransformation of Drugs

This reaction differs from general characteristics of phase II reactions.


This reaction differs from general characteristics of phase II reactions in several ways:

1. The metabolites formed are not polar or water-soluble.

2. The metabolites, in a number of instances, have equal or greater pharmacological activity than the parent drug, e.g. morphine formed from normorphine.

3. The reaction is of lesser importance in metabolism of xenobiotics. It is more important in the biosynthesis (e.g. adrenaline, melatonin) and inactivation of endogenous amines (e.g. noradrenaline, serotonin, histamine).

Methylation can be considered as intermediate of phase I and phase II reactions. It can be called as a phase I reaction as it is reverse of demethylation reaction and can be classed as a phase II reaction because of its mechanism.

Methylation of substrates proceeds in two steps:

1. Synthesis of an activated coenzyme S-adenosyl methionine (SAM), the donor of methyl group, from L-methionine and ATP.

2. Transfer of the methyl group from SAM to the substrate in presence of nonmicrosomal enzyme methyl transferase.

Important methyl transferases that catalyse methylation of xenobiotics are catechol-O-methyl transferase (COMT), phenyl-O-methyl transferase (POMT), phenyl ethanolamine-N-methyl transferase (PNMT), nonspecific transferases, etc.

Examples of substrates undergoing methylation are:


Phenols e.g. morphine

Catechols e.g. -methyl dopa, L-DOPA, isoprenaline


Primary aliphatic amines e.g. norephedrine

Secondary alicyclic amines e.g. normorphine

Aromatic heterocycles e.g. nicotine, histamine


Thiols e.g. propylthiouracil, 6-mercaptopurine

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