Drug Elimination III

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 substituents
(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 hydroxylamines
(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 hepatotoxic
and possibly carcinogenic.
The second type of oxidative biotransformation
comprises dealkylations.
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
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