Introduction

Drug

metabolism (biotransformation or detoxication) is

the biochemical changes of the drugs and other foreign

substances in the body.

This

is leading to the formation of different metabolites with

different effects.

Some

of the compounds are excreted partially unchanged and

some are known to be converted to products, which may be more
active or more toxic than the parent compounds.

The

liver is the major site of drug metabolism, but specific

drugs may undergo biotransformation in other tissues.

Importance
Drug metabolism is needed to convert non-polar

lipophilic compounds (lipid soluble) which the body

cannot excrete into more polar hydrophilic compounds
(water soluble) which the body can excrete them in
short period of time.
Because if the lipid soluble non-polar compounds are

not metabolized to the polar water soluble compounds,

they will remain in the blood and tissues and maintain
their pharmacological effects for an indefinite time.

Classification of metabolites:

Inactive metabolites
Metabolites retain similar activity
Metabolites with different activity
Bioactivated metabolites (prodrug technique)

1-Inactive metabolites:

Some metabolites are inactive,

i.e. their pharmacological active parent compound become

inactive.
Examples:
i)
Hydrolysis of procaine to p-aminobenzoic acid and
diethylethanolamine results in loss of anesthetic activity of
procaine.
O
O
N
NH

H2N-C6H5-COOH + Et2N-CH2CH2OH
CH3
CH3
Inactive metabolites

NH2

ii) Oxidation of 6-mercaptopurine to 6-mercapturic acid results

in loss of anticancer activity of this compound.
6-Mercaptopurine
6-Mercapturic acid (inactive)

2-Metabolites retain similar activity:

Some metabolite retain the pharmacological activity of their parent

compounds to a greater or lesser degree.
Examples:
i) Codeine is demethylated to the more active analgesic morphine
ii) Phenacetin is metabolized to more active paracetamol
iii) Imipramine is demethylated to the equiactive antidepressant
desipramine.

3-Metabolites with different activity:

Some metabolites develop activity different from that of their

parent drugs.
Examples:
i) Iproniazid (antidepressant) is dealkylated to isoniazid
(antitubercular)
ii) Retinoic acid (vitamin A) is isomerized to isoretinoic acid (antiacne agent).

4-Bioactivated metabolites (activation of

inactive drugs):

Some inactive compounds are converted to active drugs within

the body.
These compounds are called prodrugs.
Prodrugs may have advantages over the active form (active
metabolite) as more stable, having better bioavailability or
less side effects and toxicity.

Examples:
i) Levodopa (antiparkinson disease) is decarboxylated in the
neuron to active dopamine
ii) The prodrug sulindac a new non steroidal antiinflammatory
drug (sulfoxide) is reduced to the active sulfide
iii) Benorylate to aspirin and paracetamol
iv) The prodrug enalapril is hydrolysed to enalaprilat (potent
antihypertension).

Biotransformation Pathways
Drug metabolism reactions have been divided into two classes:
i)

Phase I reaction (functionalization ) and

ii)

Phase II reaction (conjugation)

Phase I reaction: Polar functional groups are either

introduced into the molecule or modified by oxidation,
reduction or hydrolysis.

Or convert lipophilic molecules into more polar molecules by

introducing or exposing polar functional groups.
E.g. aromatic and aliphatic hydroxylation or reduction of
ketones and aldehydes to alcohols.
Phase I reactions may increase or decrease or leave
unaltered the pharmacological activity of the drugs

1-Oxidation:
Addition of oxygen or removal of hydrogen.
Normally the first and most common step involved in the drug
metabolism

Majority of oxidation occurs in the liver and it is possible to occur in

intestinal mucosa, lungs and kidney.
Most important enzyme involved in this type of oxidation is
cytochrome P450
Increased polarity of the oxidized products (metabolites) increases
their water solubility and reduces their tubular reabsorption,
leading to their excretion in urine.

These metabolites are more polar than their parent compounds and
might undergo further metabolism by phase II pathways

2- Reduction:

is the converse of oxidation (i.e. removal of oxygen or

addition of hydrogen).
E.g. reduction of aldehydes and ketones, reduction of nitro
and azo compounds.
It is less common than oxidation, but the aim is same to
create polar functional groups that can be eliminated in
the urine.
Cytochrome P450 system is involved in some reaction.
Other reactions are catalyzed by reductases enzymes
present in different sites within the body.

3-Hydrolysis:

It is the reaction between a compound and water.

The addition of water across a bond also gives more polar
metabolites.

Different enzymes catalyze the hydrolysis of drugs:

Esterase enzymes
Amidase enzymes

11

1- Esterase enzymes:

Usually present in plasma and various tissues, are nonspecific and

catalyze de-esterification. Hydrolysis of nonpolar esters into two
polar and more water soluble compounds (i.e. acid and alcohol).
O

O
CH3

CH3

C OR + H2O

Ester of acetic acid

C OH + ROH

Acetic acid

Alcohol

Esterases are responsible for converting many prodrugs into

their active forms.
A classical example of ester hydrolysis is the metabolic
conversion of aspirin (acetylsalicylic acid) to salicylic acid and
COOH
acetic acid.
COOH
OCOCH3
H2O

OH
+

CH3COOH
Acetic acid

Aspirin

Salicylic acid

2-Amidase enzymes:
It is the hydrolysis of amides into amine and acid and this is
called Deamination.Deamination occurs primarily in the liver.
O

O
NH2

C R

Amide

+ H2O
Water

C OH + NH3
Acid

Ammonia

Amide drugs are more resistant to hydrolysis (or they are not
hydrolyzed until they reach the liver) than ester drugs which
they are susceptible to plasma esterase.
The duration of actions of ester drugs are less than the
amide analogues.
Example:
Procaine (ester type) injection or topical is usually shorter
acting than its amide analogue procainamide administered
similarily.

Phase II conjugation Reactions

When phase I reactions are not producing sufficiently hydrophilic
(water soluble) or inactive metabolites to be eliminated from the
body, the drugs or metabolites formed from phase I reaction
undergoes phas II reactions.
Generally phase I reactions provide a functional groups or handle in
the molecule that can undergo phase II reactions. Thus, phase II
reactions are those in which the functional groups of the original
drug (or metabolite formed in a phase I reaction) are masked by a
conjugation reaction.
Phase II conjugation reactions are capable of converting these
metabolites to more polar and water soluble products.
Many conjugative enzymes accomplish this objective by attaching small,
polar, and ionizable endogenous molecules such as glucuronic acid ,
sulfate, glycine, glutamine and glutathione to the phase I metabolite
or parent drug. The resulting conjugated products are very polar (water
soluble), resulting in rapid drug elimination from the body.

Phase II Conjugation Reactions

These reactions require both a high-energy molecule and an enzyme.
The high-energy molecule consists of a coenzyme which is bound to the
endogenous substrate and the parent drug or the drugs metabolite
resulted from phase I reaction.
The enzymes that catalyzed conjugation reactions are called
transferases, found mainly in the liver and to a lesser extent in the
intestines and other tissues.
Most conjugates are biologically inactive and nontoxic because they are
highly polar and unable to cross cell membrane.
Exceptions to this are acetylated and methylated conjugates
because these phase II reactions (methylation and acetylation) does
not generally increase water solubility but serve mainly to terminate or
reduce pharmacological activity (they are usually pharmacologically
inactive).

Conjugating molecules:
o 1- Glucuronic acid conjugation:

o It forms O-glucuronides with phenols Ar-OH,

alcohols R-OH, hydroxylamines H2N-OH,and

carboxylic acid RCOOH.
o It can form N-glucuronides with sulfonamides,
amines, amides, and S-glucuronides with thiols.

o 2-Sulfate conjugation:

o It is less common.
o It is restricted to phenols, alcohols, arylamines, and

N-hydroxyl compounds.
o But primary alcohols and aromatic hydroxylamines
can form unstable sulfate conjugates which can be
toxic.

Conjugating molecules:
3-Amino acid conjugation:
By the formation of peptide link. With glycine or

glutamine.

4- Glutathione conjugation:
It reacts with epoxides, alkylhalides, sulfonates,

disulfides, radical species.

These conjugates are converted to mercapturic

acid and mostly are excreted in bile. It is

important in detoxifying potentially dangerous
environmental toxins.

Conjugating molecules:

5,6- Methylation and acetylation reactions:

These decrease the polarity of the drugs except tertiary

amines which are converted to polar quaternary salts.
The groups susceptible for these reactions are phenols,
amines, and thiols.
O-methylation of meta-phenolic OH in catecholamines

does not generally increase water solubility but serve

mainly to terminate or reduce pharmacological activity (they
are usually pharmacologically inactive).

7- Cholesterol conjugation:

For carboxylic acids by ester link formation or for drug

with ester group by trans esterification.

8- Fatty acid conjugation:

For drugs with alcohol functional groups by ester link.

There are six conjugation pathways:

1)-Glucuronidation: by glucuronyl transferase.

O

HOOC

H
R

HO
HO

HOOC

OH O

HO
HO

UDP

Glucuroinc acid UDP

OH X R

X = OH, NR 2, CO2H, SH, acidic carbon atom

Glucuronyl Transferease catalyses this conjugation reaction

2)-Sulfate conjugation
O
HO

S
O

O
O

P
OH

Adenine
+

O
R

HO

S
O

H2O3PO

X
R

HO

PAPS

X = OH, arylamine, NHOH

Sulfotransferease catalyses this conjugation reaction

There are six conjugation pathways:

3)-Amino acid conjugation:
O
H

C
R

CoA

H2N

Y
CO2H

H
N

CO2H

Acyl coenzyme A

Y = H or CH2CH2CO2H

N-acyltransferase catalyses the conjugation reaction

4)-Glutathione conjugation
O
H

C
R

CoA

Acyl coenzyme A

H2N

Y
CO2H

H
N

Y
CO2H

H
Y = H or CH2CH2CO2H

Glutathione S-transferase catalyses this conjugation

reaction

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5)-Methylation
CH3
S

HO2C

Adenine

O
NH2

+
H2O3PO

HO

R X

X CH3

X = OH, NH2, SH

SAM

Methyltransferase catalyses this conjugation reaction

6)-Acetylation
O

C
H3C

CoA

Aceyl CoA

R X

Y =NH2, NHNH2, SO2NH2, CONH2

N-acyltransferase catalyses the conjugation reaction

Extrahepatic metabolism
Refers to drug biotransformation that takes
place in tissues other than the liver.
The most common sites include the plasma, GI
mucosa, nasal passages, lungs and kidneys.
However, metabolism can occur throughout
the body.

Factors influencing Drug

Metabolism

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Factors influencing Drug Metabolism

1-Chemical Structure :
The chemical structure (the absence or presence of certain
functional groups) of the drug determines its metabolic pathways.

2-Species differences (Qualitative & Quantitative):

Qualitative differences may result from a genetic deficiency of a
certain enzyme while quantitative difference may result from a
difference in the enzyme level.

3-Physiological or disease state:

1-For example, in congestive heart failure, there is decreased hepatic
blood flow due to reduced cardiac output and thus alters the extent
of drug metabolism.
2-An alteration in albumin production can alter the fraction of bound
to unbound drug, i.e., a decrease in plasma albumin can increase he
fraction of unbound free drug and vice versa.
3-pathological factors altering liver function can affect hepatic
clearance of the drug.

Factors influencing Drug Metabolism

4-Genetic variations:

Isoniazid is known to be acetylated by Nacetyltransferase into inactive metabolite.

The rate of acetylation in asian people is higher or faster

than that in eurpoean or north american people. Fast
acetylators are more prone to hepatoxicity than slow
acetylator.

5-Drug dosing:

1- An increase in drug dosage would increase drug

concentration and may saturate certain metabolic
enzymes.

2- when metabolic pathway becomes saturated, an

alternative pathway may be pursued.

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Factors influencing Drug Metabolism

6-Nutritional status:

1-Low protein diet decreases oxidative reactions or

conjugation reactions due to deficiency of certain amino
acids such as glycine.

2-Vitamin deficiency of A,C,E, and B can result in a

decrease of oxidative pathway in case of vitamin C
deficiency , while vitamin E deficiency decreases
dealkylation and hydroxylation.

3-Ca, Mg, Zn deficiencies decreases drug metabolism

capacity whereas Fe deficiency increases it.

4-Essential fatty acid (esp. Linoleic acid) deficiency

reduce the metabolism of ethyl morphine and hexobarbital
by decreasing certain drug-metabolizing enzymes.

Factors influencing Drug Metabolism

7-Age:
1- Metabolizing enzymes (sp.glucuronide conjugation)are not
fully developed at birth, so infants and young children
need to take smaller dosesthan adults to avoid toxic
effects.
2-In elderly, metabolizing enzyme systems decline.

8-Gender (sex):
Metabolic differences between females and males have been
observed for certain compounds
Metabolism of Diazepam, caffiene, and paracetamol is faster
in females than in males while oxidative metabolism of
lidocaine, chordiazepoxide are faster in men than in
females

Factors influencing Drug Metabolism

9-Drug administration route:

1-Orally administered drugs are absorbed from the

GIT and transported to the liver before entering the
systemic circulation. Thus the drug is subjected to
hepatic metabolism (first pass effect) before reaching
the site of action.

2-Sublingually and rectally administered drugs take

longer time to be metabolized than orally taken
drugs.Nitroglycerine is ineffective when taken orally
due to hepatic metabolism.

3-IVadministration avoid first pass effect because the

drug is delivered directly to the blood stream.

Factors influencing Drug Metabolism

10-Enzyme induction or inhibition
Several antibiotics are known to inhibit the activity of
cytochrome P450.
Phenobarbitone is known to be cytochrome P450
enzyme inducer while cimetidine is cyt. P450
inhibitor.
If warfarin is taken with phenobarbitone, it will be
less effective.
While if it is taken with cimetidine, it will be less
metabolized and thus serious side effects may
appear.

Strategies to manage drug

metabolism

30

Strategies to manage drug metabolism

1)-Pharmaceutical strategies:

by using different dosage forms to either avoid or compensate for

rapid metabolism.
1-Sublingual tablets (through mucous mermbrane) by delivering
drugs directly to blood and bypassing first-pass effect as
nitroglycerine (antiangina drug).
2-Transdermal patches and ointments: provide continuous supply of
drug over extended period of time and are useful for rapidly
metabolizing drugs suchj as prophylactic nitroglycerine.
3- Intramuscular injections provide a continuous supply of drug over
extended period of time such as`lipid soluble esters of
estradiol and testosterone. Hydrolysis of these prodrugs
produce a steady supply of rapidly metabolized hormones.
4-Enteric coated formulation can protect acid-sensitive drugs as
erythromycin.
5-Nasal administration allows for the delivery of peptides such as
aerosols since they need only to penetrate the thin epithelial
layer to reach the abundant capillary beds

Strategies to manage drug metabolism

2)-Pharmacological strategies
These involve the concurrent use of enzyme inhibitors to decrease

drug metabolism. Sometimes the concurrent use of an additional

agent doesnt prevent metabolism but prevents the toxicity
caused by metabolites of the therapeutic agent.

1- Levodopa, the aminoacid precursor of dopamine, in the treatment o

Parkinsons disease. Carbidopa , a dopa decarboxylase inhibitor
2- -Lactam antibiotics activity is reduced by micoorganisms capable

of secreting lactamase enzymes. Clavulanic acid is a lactamas

inhibitor used in conjunction with penicillin antibiotics.

Strategies to manage drug metabolism

3)-Chemical strategies
These are molecular modifications involving
the addition, deletion or isosteric
modification of functional groups.
Examples are:
1-chlorpropamide was designed from
tolbutamide
2-Methyl testosterone was designed from
testosterone.
33

Prodrugs strategies
Prodrugs are used instead of active form of
the
drug to:
a) Enhance membrane permeability,
b) Reduce drug toxicity
c) Overcome /mask bad taste
d) Overcome acid sensitivity
e) Prolong (short) duration.

34

Advantages of Prodrugs
1- An increase in water solubility by using sodium succinate esters as
chloramphenicol succinate IV injection.
2- An increase in lipid solubility
a-Increase duration of action by using lipid soluble esters
b-Increase oral absorption as by using esters of the highly polar drugs
or N-methylation
C-Increase topical absorption of steroids by masking OH group as
esters or acetonides.
3-A decrease in water solubility to increase palatability as in
chloramphenicol palmitate
4- Decrease GI irritation (side effect) as in aspirin
5- Site specificity as in methyl dopa
6- Increased half-life and chemical stability as in cefamandole
acetate a stable prodrug, while the parent cefamandole is unstable
solid dosage form. Hetacillin is another prodrug (for ampicillin ).