Oxidation: Aromatic Hydroxylation. Since many drugs contain aromatic rings, this
is a very common metabolic transformation. The process tends to be species specific,
with human showing a strong tendency to hydroxylation in the para position. This reaction proceeds via an arene epoxide intermediate. The anticonvulsant drug phenytoin is
metabolized by being para-hydroxylated in its aromatic rings.
Oxidation: Carbon–Nitrogen Systems. Primary amines may be hydroxylated at the
nitrogen atom (N-oxidation) to yield the corresponding hydroxylamine. Alternatively,
primary alkyl or arylalkyl amines may undergo hydroxylation at the α-carbon to give
a carbinolamine that decomposes to an aldehyde and ammonia (through the process
of oxidative deamination). Secondary aliphatic amines may lose an alkyl group first
(N-dealkylation) prior to oxidative deamination.
Oxidation: Carbon–Oxygen Systems. Molecules containing ether linkages may
undergo oxidative O-dealkylation. In this process, the carbon atom located α to the
oxygen atom is hydroxylated, followed by cleavage of the C-O bond.
Oxidation: Alcohols and Aldehydes. The oxidation of alcohols to aldehydes and of
aldehydes to carboxylic acids is routine, and is catalyzed by alcohol dehydrogenase and
aldehyde dehydrogenase, respectively.
Oxidation: Carbon–Sulfur Systems. The most common metabolic process that
affects a C-S system is S-oxidation. The S atom is oxidized to a sulfoxide. In the case
of thioketones, the C=S double bond is converted to a C=O bond. For thioethers, oxidative S-dealkylation is a possibility.
Reduction: Carbonyl groups. The carbonyl group (-(C=O)-) is reduced through a
reaction that is catalyzed by an aldo-keto reductase requiring NADH as a cofactor. A
large number of aromatic and aliphatic ketones are reduced to the corresponding alcohols; these reductions are frequently stereospecific. α,β-Unsaturated ketones are typically metabolized to saturated alcohols.
Reduction: Nitro Groups. Nitro reduction is catalyzed by the cytochrome P450
system in the presence of the NADPH cofactor; it is a multistep process in which the
reduction of the nitro group to a nitroso group is a rate-limiting step. The metabolic conversion of the nitro group in clonazepam to an amine is a representative example.
Hydrolyses: Esters and Amides. The plasma, liver, kidney, and intestines contain a
wide variety of nonspecific amidases and esterases. These catalyze the metabolism of
esters and amides, ultimately leading to the formation of amines, alcohols, and carboxylic acids. Kinetically, amide hydrolysis is much slower than ester hydrolysis. These
hydrolyses may exhibit stereoselectivity.
Conjugations. Conjugation reactions are Phase II metabolic reactions that are enzymatically catalyzed and involve the attachment of small polar molecules (glucuronic acid,
sulphate, amino acids) to the drug. This, in turn, makes the drug more water soluble and
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is a very common metabolic transformation. The process tends to be species specific,
with human showing a strong tendency to hydroxylation in the para position. This reaction proceeds via an arene epoxide intermediate. The anticonvulsant drug phenytoin is
metabolized by being para-hydroxylated in its aromatic rings.
Oxidation: Carbon–Nitrogen Systems. Primary amines may be hydroxylated at the
nitrogen atom (N-oxidation) to yield the corresponding hydroxylamine. Alternatively,
primary alkyl or arylalkyl amines may undergo hydroxylation at the α-carbon to give
a carbinolamine that decomposes to an aldehyde and ammonia (through the process
of oxidative deamination). Secondary aliphatic amines may lose an alkyl group first
(N-dealkylation) prior to oxidative deamination.
Oxidation: Carbon–Oxygen Systems. Molecules containing ether linkages may
undergo oxidative O-dealkylation. In this process, the carbon atom located α to the
oxygen atom is hydroxylated, followed by cleavage of the C-O bond.
Oxidation: Alcohols and Aldehydes. The oxidation of alcohols to aldehydes and of
aldehydes to carboxylic acids is routine, and is catalyzed by alcohol dehydrogenase and
aldehyde dehydrogenase, respectively.
Oxidation: Carbon–Sulfur Systems. The most common metabolic process that
affects a C-S system is S-oxidation. The S atom is oxidized to a sulfoxide. In the case
of thioketones, the C=S double bond is converted to a C=O bond. For thioethers, oxidative S-dealkylation is a possibility.
Reduction: Carbonyl groups. The carbonyl group (-(C=O)-) is reduced through a
reaction that is catalyzed by an aldo-keto reductase requiring NADH as a cofactor. A
large number of aromatic and aliphatic ketones are reduced to the corresponding alcohols; these reductions are frequently stereospecific. α,β-Unsaturated ketones are typically metabolized to saturated alcohols.
Reduction: Nitro Groups. Nitro reduction is catalyzed by the cytochrome P450
system in the presence of the NADPH cofactor; it is a multistep process in which the
reduction of the nitro group to a nitroso group is a rate-limiting step. The metabolic conversion of the nitro group in clonazepam to an amine is a representative example.
Hydrolyses: Esters and Amides. The plasma, liver, kidney, and intestines contain a
wide variety of nonspecific amidases and esterases. These catalyze the metabolism of
esters and amides, ultimately leading to the formation of amines, alcohols, and carboxylic acids. Kinetically, amide hydrolysis is much slower than ester hydrolysis. These
hydrolyses may exhibit stereoselectivity.
Conjugations. Conjugation reactions are Phase II metabolic reactions that are enzymatically catalyzed and involve the attachment of small polar molecules (glucuronic acid,
sulphate, amino acids) to the drug. This, in turn, makes the drug more water soluble and
148
MEDICINAL CHEMISTRY