Drug Metabolism
Dr. Ziaul Hasan
Introduction
 Metabolism refers to series of biochemical
chemicals reactions occurring in the body to convert
drug substance to more easily extractable and
notoxic forms.
 Metabolism plays an important role in elimination
of drugs and foreign substance from the body.
 Liver is the primary site of metabolism for almost
every drug.
 Several isoforms CYP450 (CYP) enzymes are
involved in drug metabolism; they are the most
important group of enzymes in phase I metabolism.
Phases of drug metabolism
Metabolism of drugs are divided into two phases
Phase-I
Phase-II
Phase-I
Phase-I converts a parent drug to a more polar
metabolites by inserting polar functional groups such
as –OH, -COOH, -SH, -NH2 etc.
The reactions of phase-I involves oxidation,
reduction and hydrolysis.
Oxidation
A large number of drug substances or xenobiotics
undergoes metabolism by oxidation. These includes
alcohol, aldehydes, olefins, amines, aromatic
compound etc.
Oxidation of alcohol
Aliphatic and aromatic alcohols undergo oxidation to
form the corresponding acid . It is catalysed by
alcohol dehydrogenase.
Oxidation of aldehyde
Aldehydes undergo oxidation to form the corresponding
acids.
CHO
COOH
O
Benzaldehyde
Bezoic acid
Oxidation of olefins
Olefins (compound containing double bond) undergo
oxidation to form the corresponding epoxide. The
epoxide my further undergoes enzymatic hydration to
form trans 1,2-dixydroxides.
Example: Carbamazepine undergoes oxidation to
form carbamzepine-10,11-epoxide, which on
enzymatic hydration forms trans-10,11-dihydroxy
carbamazepine.
Oxidation of aromatic ring
Aromatic compound undergoes oxidation to form
epoxide intermediate, which rearrange to form arenol.
R
R
R
O
Arene oxide
OH
Arenol
[O]
Arene
For example phenobarbital undergoes metabolism by
oxidation to form hydroxyphenobarbital.
2 5
2 5
Oxidation of carbon atom α to the
Carbon atomgroup
adjacent to carbonyl function undergoes
carbonyl
oxidation to form hydroxy derivatives.
e. g. Diazepam undergoes oxidation at 3rd position to form 3hydroxydiazepam.
3
3
Reduction
A large drug substancescontainingaldehyde,nitro
and azo groups undergo metabolism by reduction.
Reduction of aldehyde
Aldehydes and ketones undergoes reduction by
enzymes called aldo-keto reductase.
e.g. Bioreduction of chloral a sedative hypnotic drug
undergoes reduction to form trichloroethanol.
Reduction of nitro compound
Variuos aromatic nitro drugs undergo enzymatic
reduction to the corresponding aromatic amine .
e.g. Nitrazepam extensively metabolise to its 7-amino
metabolite.
Hydrolysis
Drugs containing ester and amide functional group
undergoes metabolism by hydrolysis.
e.g. Aspirin undergoes metabolism by hydrolysis of the
ester functional group to form salicylic acid and acetic
acid.
3
3
Phase-II
In Phase-II the metabolites formed in Phase-I are
converted to more polar and water soluble product by
attaching polar and ionisable moiety such as glucuronic
acid, sulfate, glycine and glutamic acid.
The resulting conjugated products are relatively water
soluble and readily excretable.
Glucuronic acid
Conjugation with glucuronic acid is the most common
reaction. The active form of glucuronic acid is UDPglucuronic acid.
Phenolic and alcoholic hydroxyls are the most
common
functional
group
undergoing
Glucuronidation in drug metabolism.
R
OH
R
O
glucuronide
Drugs like morphine, acetaminophen, chloramphenical
and propranolol undergo metabolism by
glucuronidation.
Glyc
ine aromatic carboxylic acids form conjugate with
Many
glycine. benzoic acid conjugates with glycine to form
hippuric acid, which is a well known metabolic reaction.
CONH CH2 COOH
COOH
+
Benzoic acid
Glycine
H2O
Hippuric acid
CONH CH2 COOH
OH
COOH
OH
+
Benzoic acid
+
H2N CH2 COOH
+
H2N CH2 COOH
Glycine
Salicyluric acid
H2O
Glutamine
Glutamine conjugation occurs mainly with phenylacetic
acid to form phenylacetyl glutamin.
O
CH2 C OH
Phenyl acetic acid
+
COOH
H2N C CH2CH2CONH2
H
Glutamic acid
O
CH2 C
COOH
H
N C CH2CH2CONH2
H
Glutamine conjugate
Glutathione
A wide range of organic compounds such as alkyl or
aryl halides, nitro compounds, alkanes get conjugated
with cysteine of glutathione.
Acetic acid
Acetyl-CoA is the active form of acetic acid that takes
part in conjugation reaction.
Drugs containing primary amino group such as
sulfonamide, hydrazides and hydrazine undergoes
metabolism by acylation.
O
O
C NHNH2
N-Acetylation
N
Isoniazid
CH3
C NHNH C
O
N
N-Acetylisoniazid
Factors affecting drug metabolism
Age differences
 Age related differences in drug metabolism is quite
apparent in the newborn.
 In new born babies deficiency of oxidative and
conjugative enzymes are responsible for reduced
metabolic capability.
 e.g. Oxidative (Cytochrome P450 ) metabolism of
tolbutamide appears to be low in newborn.
 The ability of infants to conjugate chloramphenicol
with glucuronic acid appears to be responsible for
gray baby syndrome.
Species and strain
differences
The metabolism of many drugs and xenobiotics are often
species dependant.
 Metabolism of amphetamine occurs by two different pathway
i.e. Oxidative deamination or aromatic hydroxylation.
 In human, guinea pig, and rabbit deamination appears to be
the predominate pathway.
 However in in rat, aromatic hydroxylation appears to be more
important.
CH2
O
C CH3
Oxidative
deamination
CH2
NH2
CH CH3
HO
CH2
NH2
CH CH3
Rat
Human, Rabbit
Phenylacetone
Aromatic
Hydroxylation
Amphitamine
p-Hydroxyamphetamine
Hereditary
or
genetic
differences
 Marked difference in metabolism of several drugs in
human occurs due to genetic factor .
 Genetic factors influence the rate of oxidation of
phenytoin, phenylbutazone, nortriptyline etc.
 The rate of oxidationof these drugs varies widely
among different individual.
Gender differences
 The rate of metabolism of drugs also varies due to
gender difference in animals.
 Adult male rat metabolizeseveraldrugs at much
faster rat than female rat.
 e.g. N-demethylationof aminopyrin,oxidation of
hexobarbital, glucuronidation of o-aminophenol.
Enzyme induction
 The activity of hepatic enzymes such as cytochrome
P-450 can be increased by exposure to diverse drugs ,
pesticides etc.
 The process by which the activity of these drug
metabolising enzymes is increased is termed enzyme
induction.
 e.g. Phenobarbital can increase the metabolism of
cortisol,Vitamin D in human.
 Phenobarbital induces the glucuronyltransferase
enzyme, thereby enhances the conjugation with
glucuronic acid.
 Other chemicals such as polycyclic aromatic
hydrocarbons and pesticide may induce certain oxidative
pathway and thereby alter drug response.
Enzyme inhibition
 Several drugs and food material can inhibit drug
metabolism. With decreased drug metabolism, a drug
often accumulated leading to prolonged duration of
action and serious adverse effect.
 Enzyme inhibition can occur by diverse mechanism
such as inactivation of drug metabolising enzymes,
interference with protein synthesis and hepatotoxicity
leading to impairment of enzyme activity.
 e.g. Phenylbutazone inhibits the metabolism of
warfarin. This can lead to increased hemorrhage in
patient on both warfarin and phenylbutazone
therapy.
 Similarly the metabolism of phenytoin is inhibited
by chloramphenicol and isoniazid.
Steriochemical aspects
 Many drugs are often administered as racemic mixture
in humans. The two enantiomer present in the racemic
mixture may differ in pharmacological activity.
 The individual enantiomers of racemic mixture also may be
metabolised by different pathway.
 e.g. In dogs the (+) enantiomer of sedative hypnotic
glutethimide is hydroxylated primarily at α to the
carbonyl to yield 5-hydroxyglutethimide, whereas the (-)
enantiomer undergoes aliphatic hydroxylation of its C-2 ethyl
group.