Hydrolytic Reactions

PHASE I REACTIONS

HYDROLYTIC REACTIONS

These reactions differ from oxidative and reductive reactions in 3 respects:

1. The reaction does not involve change in the state of oxidation of the substrate.

2. The reaction results in a large chemical change in the substrate brought about by loss of relatively large fragments of the molecule.

3. The hydrolytic enzymes that metabolise xenobiotics are the ones that also act on endogenous substrates. Moreover, their activity is not confined to liver as they are found in many other organs like kidney, intestine, etc.

A number of functional groups are hydrolysed viz. esters, ethers, amides, hydrazides, etc.

Hydrolysis of Esters and Ethers

Esters on hydrolysis yield alcohol and carboxylic acid. The reaction is catalysed by esterases.

The ester substrates undergoing hydrolysis can be classified as under:

Organic esters with both large acidic and alcoholic groups on hydrolysis results in metabolites with complete loss of activity. Esters where one of the groups is relatively large, retain much of their activity when hydrolysed since such a group is generally a pharmacophore (having pharmacological activity). In many cases, such esters are prodrugs which rely on hydrolysis for their transformation into active form, e.g. chloramphenicol palmitate.

Aromatic esters are hydrolysed by arylesterases and aliphatic esters by carboxylesterases.

Examples of various classes of esters undergoing hydrolysis are given below.

Organic acid (carboxylic acid) esters

Esters with a large acidic (and small alcohol) group e.g. clofibrate.

Esters with large alcoholic (and small acidic) group e.g. aspirin.

Esters with large acidic and alcoholic groups (generally amine alcohols) e.g. succinylcholine.

Inorganic Acid Esters

Phosphates e.g. stilbestrol diphosphate.

Sulphates e.g. isopropyl methanesulphonate.

Nitrates e.g. pentaerythritol tetranitrate

Ethers undergoing hydrolysis are glycosides such as digoxin and digitoxin and O-glucuronides.

Hydrolysis of Amides (C-N bond cleavage)

Amides are hydrolysed slowly in comparison to esters. The reaction, catalysed by amidases, involves C-N cleavage to yield carboxylic acid and amine.

Primary amides are rare. Secondary amides form the largest group of amide drugs.

Examples of amide hydrolysis are given below.

Secondary amides with aliphatic substituent on N-atom e.g. procainamide (hydrolysed slowly in comparison to procaine)

Secondary amides with aromatic substituent on N-atom (anilides) e.g. lidocaine.

Tertiary amides (N-atom contained in a ring) e.g. carbamazepine.

Hydrazides are also a class of amides e.g. isocarboxazide.

Hydrolytic Cleavage of Non-aromatic Heterocycles

Nonaromatic heterocycles also contain amide functions, e.g. lactams (cyclic amides). Several lactams that undergo hydrolysis are:

1. Four-membered lactams (ß-lactam) e.g. penicillins.

2. Five-membered lactams e.g. succinimides.

3. Six-membered lactams e.g. thalidomide.

4. Seven-membered lactams e.g. chlordiazepoxide

Hydrolytic Dehalogenation

Chlorine atoms attached to aliphatic carbons are dehalogenated easily, e.g. DDT.

Miscellaneous Hydrolytic Reactions

These reactions include hydration of epoxides and arene oxides, hydrolysis of sulphonyl ureas, carbamates, hydroxamates and of glucuronide and sulphate conjugates.