 Drug metabolism is the biochemical modification

of pharmaceutical substances by living organisms,

usually through specialized enzymatic systems.
 Drug metabolism often converts lipophilic
chemical compounds into more readily excreted
hydrophilic products.
 The rate of metabolism determines the duration
and intensity of a drug's pharmacological action.
 When drugs enter the body, they are subjected to
attack from a range of metabolic enzymes.
➢ The role of these enzymes is to degrade or modify
the foreign structure, such that it can be more easily
excreted. As a result
➢ Most drugs undergo some form of metabolic reaction,
resulting in structures known as metabolites .
➢ Very often, these metabolites lose the activity of the
original drug, but, in some cases, they may retain a
certain level of activity.
 In exceptional cases, the metabolite may even be
more active than the parent drug.
 Some metabolites can possess a different activity
from the parent drugs, resulting in side
effects or toxicity.
 The liver is the most important organ for metabolism of both
endogenous and exogenous compounds present in the blood.
 The majority of drugs are metabolized in the liver by the hepatic
microsomal enzymes located in the hepatic endoplasmic reticulum.
 Some orally administered drugs are susceptible to biotransformation
in GIT before their absorption such as chloramphenicol palmitate.
 Others are absorbed from the alimentary canal and transferred
directly to the liver through the portal vein where they are susceptible to
hepatic metabolism before reaching to their sites of action by systemic
circulation e.g. lidocaine, salicylamide and isoproterenol. first-pass or
pre-systemic metabolism

 To avoid this problem, the compounds are administered in inactive

form which on first-pass metabolism, are converted to the active drug.
 Extrahepatic metabolism:
 Some pro-drugs of ester type such as chloramphenicol palmitate are
activated in the intestine via hydrolysis by esterases and lipase enzymes.
On the other hand, isoproterenol is inactivated in the intestine by
conjugation with sulfate.

 Bacterial flora of the intestine and colon can also play a significant role in
the fate of drugs. The anti-infective and anti-inflammatory effects of
sulfasalazine used in treating ulcerative colitis are mainly due to liberation
of sulfapyridine and 5-aminosalicylic acid under the influence of bacterial
reduction in the colon.
 Although drug metabolism usually leads to deactivation or
detoxification, it may leads also to the formation of a metabolite having
therapeutic or toxic effects

Metabolism

Inactive/ low More active Active Toxic

active metabolites metabolites metabolites
metabolites

Same Different
activity activity
 In some cases, metabolism may produce
metabolies, which are less active than the parent
drugs. Hydroxyamphetamine is a representative
example of the case.
 Many inactive prodrugs are converted in the body to
active metabolites through the metabolism.
 The antimicrobial effect of the azo dye prontosil red is
due to its conversion via reduction process to
sulfanilamide.
 Cyclization of chlorguanide gives the potent antimalarial,
cycloguanile.
 Decarboxylation of chlorazepate results in formation of
the active sedative-hypnotic, nordazepam.
 Moreover, biotransformation may convert some
bioactive drugs to more active metabolites as in
case of chloral hydrate and imipramine
 Drug metabolite may induce another pharmacological action which is
different from that of the parent drug. The sedative-hypnotic drug,
methaqualone yields its 2-hydroxymethyl metabolite which possesses
hypolipidimic effect.
➢ Although metabolism is considered as detoxification process, it can
also be considered as a source of toxicity.
➢ Metabolism of many drugs may lead to formation of toxic,
carcinogenic or even teratogenic metabolites.
 The carcinogenic effect of diethylstilbesterol is probably due to
epoxidation of the olefinic double bond.
 The hepatotoxic side effect of the antipyretic-analgesic drug,
acetaminophen, is mainly induced by its oxidation to an electrophilic
imidoquinone.
 The pathways of drug metabolism have been divided into two
categories namely phase-1 and phase-2 reactions.
 phase-1 usually convert the parent drug into a more polar
metabolite by introducing or unmasking a functional group (-OH, -
NH2, COOH -SH) thus, phase-1 is considered as functionalization
process.
 The reactions involved in phase-1 include oxidation, reduction
and hydrolysis.
 Phase 2 reactions are synthetic reactions (an endogenous
substrate such as glucuronic acid, sulfuric acid, acetic acid, or
amino acid is attached to a functional group on the drug or phase I
metabolite).
 Phase-2 is considered as conjugation process. The conjugated
products are generally inactive and non-toxic.
 Phase-2 reactions can be regarded as truly detoxifying pathways in
drug metabolism. Phase-1 and phase-2 reactions are
complementary.
 In this phase, the non-polar drugs undergo certain reaction, which render
them more polar. This takes place via two pathways:

 1-Introduction of a more polar functional group into the drug molecule

(-OH, -NH2, COOH –SH....etc.).

 2-Modification of an existing group and converting it to a more polar

one. this can be achieved by:

❖ Reduction of ketones or aldehydes to alcohols,

❖ Reduction of nitro or azo compounds to the corresponding amines,

❖ Oxidation of aldehydes, alcohols or ketones to the carboxylic acids

❖ Hydrolysis of esters to alcohols and carboxylic acids hydrolysis of amides to

amines and carboxylic acids.
  Oxidation is the most common reaction in drug metabolism

 Most of the oxidation reactions take place in the liver and catalyzed
by non-specific enzymes present in the hepatic microsomes. These
enzymes are mixed function oxidases representing a unique family of
heme proteins called cytochrome P-450.

 There are many non-microsomal enzymes that can share in oxidation

reactions such as alcohol and aldehyde dehydrogenase, mono-amine
oxidases, diamine oxidases and other enzymes.
Oxidation reactions include the following
types

Aromatic Alicyclic
Oxidation Oxidation

Olefinic Aliphatic
Oxidation Oxidation

Benzylic Oxidative
Oxidation dehalogenation

Carbon-
heteroatom
systems oxidation
Aromatic oxidation:
 Most drugs containing aromatic moieties are susceptible to aromatic
oxidation (aromatic hydroxylation).

➢ Important therapeutic agents such as propranolol, phenobarbital,

phenytoin are representatives of drugs that undergo aromatic
hydroxylation
 All aromatic hydroxylation reaction are believed to proceed initially
through an epoxide intermediate called an arene oxide, which
rearranges spontaneously to arenol product in most cases

Substituents attached to the aromatic ring may influence the ease of

hydroxylation. As a general rule, aromatic hydroxylation reactions appear to
proceed most readily in activated (electron-rich) rings, whereas deactivated
aromatic rings (e.g., those containing electron-withdrawing groups Cl,,
COOH, SO2NHR) are generally slow or resistant to hydroxylation.
 The metabolic oxidation of olefinic carbon–carbon double bonds leads to the
corresponding epoxide which undergo further hydration by epoxide hydrase to
form trans- 1,2-dihydrodiols (also called 1,2-diols or 1,2-dihydroxy compounds).
 Examples:
 Toxicity of some olefinic compounds may result from their metabolic
conversion to chemically reactive epoxides.
 One example is aflatoxin B1. This naturally occurring carcinogenic
agent contains an olefinic (C2–C3) double bond adjacent to a cyclic
ether oxygen. The hepatocarcinogenicity of aflatoxin B1 has been
clearly linked to its metabolic oxidation to the corresponding 2,3-oxide,
which is extremely reactive.
 Carbon atoms attached to aromatic rings (benzylic position)
are susceptible to oxidation, thereby forming the corresponding
alcohol (or carbinol) metabolite which is often oxidized further to
aldehydes and carboxylic acids (CH2OH → CHO → COOH).
e,g. tolbutamide (Orinase) is oxidized extensively to the
corresponding alcohol and carboxylic acid.
 Both metabolites have been isolated from human urine. On the
other hand, the benzylic carbon may be oxidized only to
hydroxymethyl derivatives e.g. methaqualone.
 Alkyl or aliphatic carbon centers are subjected to mixed function oxidation.
Metabolic oxidation at the terminal methyl group and oxidation of the
penultimate carbon atom (i.e., next-to-the-last carbon)
 The initial alcohol metabolites formed from these oxidations are susceptible
to further oxidation to yield aldehyde, ketones, or carboxylic acids.
 Alternatively, the alcohol metabolites may undergo glucuronide conjugation.
 The cyclohexyl group is commonly found in many medicinal agents, and is
also susceptible to mixed-function oxidation (alicyclic hydroxylation).
Introduction of a hydroxyl group into a monosubstituted cyclohexane ring
generally occurs at C-3 or C-4 and can lead to cis and trans conformational
stereoisomers, .e.g. acetohexamide and minoxidil metabolism.
  The mixed-function oxidase system also oxidizes carbon atoms
adjacent to carbonyl and imino functionalities. An important class of
drugs undergoing this type of oxidation is the benzodiazepines.
 Another example is sedative-hypnotic, glutethimide
 Metabolic oxidation of carbon–nitrogen, carbon–
oxygen, and carbon–sulfur systems principally
involves two basic types of biotransformation
processes:
 Hydroxylation of carbon atom attached directly to
the heteroatom (N, O, S).
 Hydroxylation or oxidation of the heteroatom (N, S
only, e.g., N-hydroxylation, N-oxide formation,
sulfoxide, and sulfone formation).
nitrogen-containing compounds classes:
1. Aliphatic and alicyclic amines
2. Aromatic and heterocyclic nitrogen compounds
3. Amides.

 Tertiary aliphatic amines

 The oxidative removal of alkyl groups (particularly methyl groups)
from tertiary aliphatic and alicyclic amine is an oxidative N-
dealkylation process
 small alkyl groups, such as methyl, ethyl, and isopropyl, are removed
rapidly.
 The first alkyl group from a tertiary amine is removed more rapidly
than the second alkyl group. e.g. imipramine and lidocaine.
 Many times, bisdealkylation of a tertiary amine
leads to the corresponding primary aliphatic amine
metabolite, which is susceptible to further
oxidation. e.g. bromopheniramine
  Secondary amines are susceptible to oxidative N-
dealkylation, oxidative deamination. e.g.
methamphetamine

➢ Some secondary alicyclic amines are metabolized to their

corresponding lactam:
 The primary amine metabolites formed from oxidative dealkylation
are susceptible to oxidative deamination.
 If alpha carbon hydroxylation cannot occur, then oxidative
deamination is not possible.
 Metabolic N-oxidation of secondary aliphatic and alicyclic amines
leads to a number of N-oxygenated products: N-hydroxylamine and
the corresponding nitron derivative.
 ɑ-Substituents of primary amine often determine
whether carbon or nitrogen oxidation will occur
 Tert. aromatic amines undergo oxidative N-dealkylation as well as
N-oxidation
 Secondary aromatic amines may undergo oxidative N-dealkylation or it
may be subjected to N-hydroxylation to give the corresponding N-
hydroxylamines, further oxidation to nitrone product, which may be hydrolyzed
to primary hydroxylamines.

Primary aromatic amines undergo N-hydroxylation and then oxidation to nitroso

derivative
 N-oxidation of the nitrogen atoms present in aromatic
heterocyclic moieties of many drugs occurs to a minor
extent.
 Amide functionality is susceptible to oxidative N-
dealkylation
 Hydroxylation of aromatic amide occurs to a minor extent because
this biotransformation may led to the formation of chemically reactive
intermediates.
 Oxidative O-dealkylation of carbon–oxygen systems involves an initial α-
carbon hydroxylation to form either a hemiacetal or a hemiketal, which
undergoes spontaneous carbon–oxygen bond cleavage to yield the
dealkylated oxygen species (phenol or alcohol) and a carbon moiety
(aldehyde or ketone)

• Small alkyl groups (e.g., methyl or ethyl) attached to oxygen are O-dealkylated
rapidly. For example, morphine is the metabolic product of O-demethylation of
codeine.
 Carbon–sulfur functional groups are susceptible to metabolic S-
dealkylation, desulfuration, and S-oxidation reactions.

➢ S-dealkylation involves α-carbon hydroxylation.

e.g. 6-methylthiopurine
➢ Many sulfides and sulfur containing heterocycles undergo S-
oxidation to form corresponding sulfoxide or dioxide
metabolites.
 The alicyclic drug is dehydrogenated to an aromatic
metabolite. e.g. contraceptive drug, norgestrel
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