hooc-ch^h nh2 Angiotensinase


Procaine p-Aminobenzoic acid ^^^^^



Acetylsalicylic acid tk

Acetic acid Salicylic acid


N-Propylalanine Toluidine

A. Examples of chemical reactions in drug biotransformation (hydrolysis)

A. Examples of chemical reactions in drug biotransformation (hydrolysis)

Oxidation reactions can be divided into two kinds: those in which oxygen is incorporated into the drug molecule, and those in which primary oxidation causes part of the molecule to be lost. The former include hydroxylations, epoxidations, and sulfoxidations. Hydroxylations may involve alkyl substitu-ents (e.g., pentobarbital) or aromatic ring systems (e.g., propranolol). In both cases, products are formed that are conjugated to an organic acid residue, e.g., glucuronic acid, in a subsequent Phase II reaction.

Hydroxylation may also take place at nitrogen atoms, resulting in hydroxyl-amines (e.g., acetaminophen). Benzene, polycyclic aromatic compounds (e.g., benzopyrene), and unsaturated cyclic carbohydrates can be converted by mono-oxygenases to epoxides, highly reactive electrophiles that are hepato-toxic and possibly carcinogenic.

The second type of oxidative biotransformation comprises dealkyla-tions. In the case of primary or secondary amines, dealkylation of an alkyl group starts at the carbon adjacent to the nitrogen; in the case of tertiary amines, with hydroxylation of the nitrogen (e.g., lidocaine). The intermediary products are labile and break up into the dealkylated amine and aldehyde of the alkyl group removed. O-dealkylation

Mechanism Phenacetin

and S-dearylation proceed via an analogous mechanism (e.g., phenacetin and azathioprine, respectively).

Oxidative deamination basically resembles the dealkylation of tertiary amines, beginning with the formation of a hydroxylamine that then decomposes into ammonia and the corresponding aldehyde. The latter is partly reduced to an alcohol and partly oxidized to a car-boxylic acid.

Reduction reactions may occur at oxygen or nitrogen atoms. Keto-oxy-gens are converted into a hydroxyl group, as in the reduction of the pro-drugs cortisone and prednisone to the active glucocorticoids cortisol and prednisolone, respectively. N-reductions occur in azo- or nitro-compounds (e.g., ni-trazepam). Nitro groups can be reduced to amine groups via nitroso and hydrox-ylamino intermediates. Likewise, deha-logenation is a reductive process involving a carbon atom (e.g., halothane, p. 218).

Methylations are catalyzed by a family of relatively specific methyl-transferases involving the transfer of methyl groups to hydroxyl groups (O-methylation as in norepinephrine [noradrenaline]) or to amino groups (N-methylation of norepinephrine, hista-mine, or serotonin).

In thio compounds, desulfuration results from substitution of sulfur by oxygen (e.g., parathion). This example again illustrates that biotransformation is not always to be equated with bio-inactivation. Thus, paraoxon (E600) formed in the organism from parathion (E605) is the actual active agent (p. 102).


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