OTHER PHASE ONE CHANGES

Although demethylation is a common metabolic process, methylation is also found particularly in the metabolism of the catecholamine neurotransmitters. Catechol O-methyl transferase (COMT) is a major metabolic deactivation for the catecholamines and its consequences are discussed later in the context of these compounds. Carboxyl esterases and peptidases lead to the deactivation of many drugs. For example, the ester procaine 2.31, which is an anaesthetic, is hydrolysed to p-aminobenzoic acid 2.32. The metabolism of the local anaesthetic, lidocaine (xylocaine) (Scheme 1) brings together several of the steps that have been outlined.

Drug metabolism can bring about a change in activity. Iproniazid 2.33 is an anti-depressant while its dealkylation product, isoniazid 2.34 has anti-tubercular activity.

Sufficient data on drug metabolism is now available for it to be possible to use molecular modelling techniques to predict the likely metabolism of a drug. Some cytochromes have been cloned and bacterial models can be used to identify putative mammalian metabolites. A drug may be incubated with a microorganism containing the common mammalian cytochromes as a first step in the identification of its metabolites.

Scheme 1: The metabolism of lidocaine