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 ma!or 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.
"lassification of metabolites#

Inactive metabolites

$etabolites retain similar activity

$etabolites with different activity

%ioactivated metabolites (prodrug techni&ue)

'(Inactive metabolites# Some metabolites are inactive
i.e. their pharmacological active parent compound become
inactive.
)xamples#
i) *ydrolysis of procaine to p(aminoben+oic acid and
diethylethanolamine results in loss of anesthetic activity of
procaine.
ii) ,xidation of -(mercaptopurine to -(mercapturic acid results
in loss of anticancer activity of this compound.
-($ercaptopurine -($ercapturic acid (inactive)
N H
2
O
N
O
N H
N
O
C H
3
C H
3
*./("-*0(",,* 1 )t./("*."*.,*
Inactive metabolites
.($etabolites retain similar activity#
Some metabolite retain the pharmacological activity of their parent
compounds to a greater or lesser degree.
)xamples#
i) "odeine is demethylated to the more active analgesic morphine
ii) 2henacetin is metaboli+ed to more active paracetamol
iii) Imipramine is demethylated to the e&uiactive antidepressant
desipramine.
3($etabolites with different activity#
Some metabolites develop activity different from that of their
parent drugs.
)xamples#
i) Ipronia+id (antidepressant) is dealkylated to isonia+id
(antitubercular)
ii) 4etinoic acid (vitamin 5) is isomeri+ed to isoretinoic acid (anti(
acne agent).
6(%ioactivated metabolites (activation of inactive drugs)#
Some inactive compounds are converted to active drugs within
the body.
These compounds are called prodrugs.
2rodrugs may have advantages over the active form (active
metabolite) as more stable having better bioavailability or
less side effects and toxicity.
)xamples#
i) 7evodopa (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) %enorylate to aspirin and paracetamol
iv) The prodrug enalapril is hydrolysed to enalaprilat (potent
antihypertension).
%iotransformation 2athways
Drug metabolism reactions have been divided into two classes#
i) 2hase I reaction (functionali+ation ) and
ii) 2hase II reaction (con!ugation)

2hase I reaction# 2olar functional groups are either

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

,r convert lipophilic molecules into more polar molecules by

introducing or exposing polar functional groups.

).g. aromatic and aliphatic hydroxylation or reduction of

ketones and aldehydes to alcohols.

2hase I reactions may increase or decrease or leave

unaltered the pharmacological activity of the drugs
'(,xidation#
5ddition of oxygen or removal of hydrogen.
/ormally the first and most common step involved in the drug
metabolism
$a!ority of oxidation occurs in the liver and it is possible to occur
in intestinal mucosa lungs and kidney.
$ost important en+yme involved in this type of oxidation is
cytochrome 2608
Increased polarity of the oxidi+ed 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
.( 4eduction#
is the converse of oxidation (i.e. removal of oxygen or
addition of hydrogen).
).g. reduction of aldehydes and ketones reduction of
nitro and a+o compounds.
It is less common than oxidation but the aim is same to
create polar functional groups that can be eliminated
in the urine.
"ytochrome 2608 system is involved in some reaction.
,ther reactions are cataly+ed by reductases en+ymes
present in different sites within the body.
11
3(*ydrolysis#
It is the reaction between a compound and water.
The addition of water across a bond also gives more polar
metabolites.
Different en+ymes cataly+e the hydrolysis of drugs#
)sterase en+ymes
5midase en+ymes
'( )sterase en+ymes#

9sually present in plasma and various tissues are nonspecific and

cataly+e de(esterification. *ydrolysis of nonpolar esters into two
polar and more water soluble compounds (i.e. acid and alcohol).
O
C OR CH
3
H
2
O
O
C OH CH
3
ROH
+
+
Ester of acetic acid
Acetic acid Alcohol
!sterases are responsible for converting many prodrugs into
their active forms.
" classical example of ester hydrolysis is the metabolic
conversion of aspirin (acetylsalicylic acid) to salicylic acid and
acetic acid.
COOH
OCOCH
3
COOH
OH
H
2
O
CH
3
COOH
+
Aspirin
Salicylic acid
Acetic acid
.(5midase en+ymes#
It is the hydrolysis of amides into amine and acid and
this is called Deamination.Deamination occurs primarily in
the liver.
O
C R NH
2
H
2
O
O
C OH R NH
3
+
+
Amide Water Acid Ammonia
"mide 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.
#he duration of actions of ester drugs are less than the
amide analogues.
!xample$
%rocaine (ester type) in&ection or topical is usually shorter
acting than its amide analogue procainamide administered
similarily.
2hase II con!ugation 4eactions
:hen 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.
;enerally 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 con!ugation reaction.
2hase II con!ugation reactions are capable of converting these
metabolites to more polar and water soluble products.
$any con!ugative en+ymes accomplish this ob!ective by attaching
small polar and ioni+able endogenous molecules such as glucuronic
acid sulfate glycine glutamine and glutathione to the phase I
metabolite or parent drug. The resulting con!ugated products are
very polar (water soluble) resulting in rapid drug elimination from
the body.
2hase II "on!ugation 4eactions
These reactions re&uire both a high(energy molecule and an
en+yme.
The high(energy molecule consists of a coen+yme which is bound to
the endogenous substrate and the parent drug or the drug<s
metabolite resulted from phase I reaction.
The en+ymes that cataly+ed con!ugation reactions are called
transferases found mainly in the liver and to a lesser extent in the
intestines and other tissues.
$ost con!ugates are biologically inactive and nontoxic because they
are highly polar and unable to cross cell membrane.
)xceptions to this are acetylated and methylated con!ugates
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).
"on!ugating molecules#
o
'( ;lucuronic acid con!ugation#
o
It forms ,(glucuronides with phenols 5r(,*
alcohols 4(,* hydroxylamines *./(,*and
carboxylic acid 4",,*.
o
It can form /(glucuronides with sulfonamides
amines amides and S(glucuronides with thiols.
o
.(Sulfate con!ugation#
o
It is less common.
o
It is restricted to phenols alcohols arylamines and
/(hydroxyl compounds.
o
%ut primary alcohols and aromatic hydroxylamines
can form unstable sulfate con!ugates which can be
toxic.
"on!ugating molecules#

3(5mino acid con!ugation#

%y the formation of peptide link. :ith glycine or

glutamine.

6( ;lutathione con!ugation#

It reacts with epoxides alkylhalides sulfonates

disulfides radical species.

These con!ugates are converted to mercapturic

acid and mostly are excreted in bile. It is
important in detoxifying potentially dangerous
environmental toxins.
0-( $ethylation and acetylation reactions#

These decrease the polarity of the drugs except tertiary

amines which are converted to polar &uaternary salts.

The groups susceptible for these reactions are phenols

amines and thiols.

,(methylation of meta(phenolic ,* in catecholamines

does not generally increase water solubility but serve

mainly to terminate or reduce pharmacological activity
(they are usually pharmacologically inactive).
=( "holesterol con!ugation#

>or carboxylic acids by ester link formation or for

drug with ester group by trans esterification.
?( >atty acid con!ugation#

>or drugs with alcohol functional groups by ester

link.
"on!ugating molecules#
There are six con!ugation pathways#
')(;lucuronidation# by glucuronyl transferase.
O
HO
HO
HOOC
H
O
UD OH
R ! +
O
HO
HO
HOOC
H
!
OH
R
! " OH# NR
2
# CO
2
H# SH# acidic car$on atom %l&c&roinc acid UD
.)(Sulfate con!ugation
O
Adenine

O
O S
O
HO
O OH
HO H
2
O
3
O
AS
+ R ! S !
O
HO
R
O
! " OH# arylamine# NHOH
;lucuronyl Transferease catalyses this con&ugation reaction
Sulfotransferease catalyses this con&ugation reaction
20
There are six con!ugation pathways#
3)(5mino acid con!ugation#
C
S
CoA
O
R
+
H
2
N CO
2
H
'
H
N CO
2
H
'
H
C
R
O
H
' " H or CH
2
CH
2
CO
2
H
Acyl coen(yme A
/(acyltransferase catalyses the con&ugation reaction
6)(;lutathione con!ugation
C
S
CoA
O
R
+
H
2
N CO
2
H
'
H
N CO
2
H
'
H
C
R
O
H
' " H or CH
2
CH
2
CO
2
H
Acyl coen(yme A
;lutathione S(transferase catalyses this con&ugation
reaction
0)($ethylation
-)(5cetylation
/(acyltransferase catalyses the con&ugation reaction
$ethyltransferase catalyses this con&ugation reaction
O
Adenine
S
+
NH
2
HO
2
C
CH
3
HO
H
2
O
3
O
R ! +
R ! CH
3
SA)
! " OH# NH
2
# SH
Aceyl CoA
' "NH
2
# NHNH
2
# SO
2
NH
2
# CONH
2
R
!
C
R
O
+
C
S
CoA
O
H
3
C
R !
)xtrahepatic metabolism

4efers to drug biotransformation that takes place in tissues other than the liver.

The most common sites include the plasma ;I mucosa nasal passages lungs and kidneys. *owever metabolism can
occur throughout the body.
23
'actors influencing Drug
(etabolism
>actors influencing Drug $etabolism

'("hemical Structure #

The chemical structure (the absence or presence of certain

functional groups) of the drug determines its metabolic pathways.

.(Species differences (@ualitative A @uantitative)#

@ualitative differences may result from a genetic deficiency of a

certain en+yme while &uantitative difference may result from a
difference in the en+yme level.

3(2hysiological or disease state#

'(>or example in congestive heart failure there is decreased

hepatic blood flow due to reduced cardiac output and thus alters
the extent of drug metabolism.

.(5n 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.
25
>actors influencing Drug $etabolism

6(;enetic variations#

Isonia+id is known to be acetylated by /(

acetyltransferase into inactive metabolite.

The rate of acetylation in asian people is higher or

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

0(Drug dosing#

'( 5n increase in drug dosage would increase drug

concentration and may saturate certain metabolic
en+ymes.

.( when metabolic pathway becomes saturated an

alternative pathway may be pursued.
>actors influencing Drug $etabolism
-(/utritional status#
'(7ow protein diet decreases oxidative reactions or
con!ugation reactions due to deficiency of certain
amino acids such as glycine.
.(Bitamin deficiency of 5") and % can result in a
decrease of oxidative pathway in case of vitamin "
deficiency while vitamin ) deficiency decreases
dealkylation and hydroxylation.
3("a $g Cn deficiencies decreases drug metabolism
capacity whereas >e deficiency increases it.
6()ssential fatty acid (esp. 7inoleic acid) deficiency
reduce the metabolism of ethyl morphine and
hexobarbital by decreasing certain drug(metaboli+ing
en+ymes.
>actors influencing Drug $etabolism
=(5ge#
'( $etaboli+ing en+ymes (sp.glucuronide con!ugation)are not
fully developed at birth so infants and young children
need to take smaller dosesthan adults to avoid toxic
effects.
.(In elderly metaboli+ing en+yme systems decline.

?(;ender (sex)#
$etabolic differences between females and males have
been observed for certain compounds
$etabolism of Dia+epam caffiene and paracetamol is
faster in females than in males while oxidative
metabolism of lidocaine chordia+epoxide are faster in
men than in females
>actors influencing Drug $etabolism
D(Drug administration route#
'(,rally administered drugs are absorbed from the
;IT and transported to the liver before entering the
systemic circulation. Thus the drug is sub!ected to
hepatic metabolism (first pass effect) before reaching
the site of action.
.(Sublingually and rectally administered drugs take
longer time to be metaboli+ed than orally taken
drugs./itroglycerine is ineffective when taken orally
due to hepatic metabolism.
3(IBadministration avoid first pass effect because the
drug is delivered directly to the blood stream.
>actors influencing Drug $etabolism
'8()n+yme induction or inhibition
Several antibiotics are known to inhibit the activity of
cytochrome 2608.
2henobarbitone is known to be cytochrome 2608
en+yme inducer while cimetidine is cyt. 2608
inhibitor.
If warfarin is taken with phenobarbitone it will be
less effective.
:hile if it is taken with cimetidine it will be less
metaboli+ed and thus serious side effects may
appear.
30
)trategies to manage drug
metabolism
Strategies to manage drug metabolism
')(2harmaceutical strategies#
by using different dosage forms to either avoid or compensate
for rapid metabolism.
'(Sublingual tablets (through mucous mermbrane) by delivering
drugs directly to blood and bypassing first(pass effect as
nitroglycerine (antiangina drug).
.(Transdermal patches and ointments# provide continuous supply
of drug over extended period of time and are useful for
rapidly metaboli+ing drugs such! as prophylactic
nitroglycerine.
3( Intramuscular in!ections provide a continuous supply of drug
over extended period of time such asElipid soluble esters of
estradiol and testosterone. *ydrolysis of these prodrugs
produce a steady supply of rapidly metaboli+ed hormones.
6()nteric coated formulation can protect acid(sensitive drugs as
erythromycin.
0(/asal 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
.)(2harmacological strategies
These involve the concurrent use of en+yme inhibitors to decrease
drug metabolism. Sometimes the concurrent use of an
additional agent doesn<t prevent metabolism but prevents the
toxicity caused by metabolites of the therapeutic agent.
'( 7evodopa the aminoacid precursor of dopamine in the
treatment of 2arkinson<s disease. "arbidopa a dopa
decarboxylase inhibitor
.( (7actam antibiotics activity is reduced by micoorganisms
capable of secreting Flactamase en+ymes. "lavulanic acid is a
Flactamase inhibitor used in con!unction with penicillin
antibiotics.
33
Strategies to manage drug metabolism
3)("hemical strategies
These are molecular modifications involving
the addition deletion or isosteric
modification of functional groups.
)xamples are#
'(chlorpropamide was designed from
tolbutamide
.($ethyl testosterone was designed from
testosterone.
34
2rodrugs
2rodrugs strategies
2rodrugs are used instead of active form of the
drug to#
a) )nhance membrane permeability
b) 4educe drug toxicity
c) ,vercome Gmask bad taste
d) ,vercome acid sensitivity
e) 2rolong (short) duration.
5dvantages of 2rodrugs
'( 5n increase in water solubility by using sodium succinate esters
as chloramphenicol succinate IB in!ection.
.( 5n 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 /(methylation
"(Increase topical absorption of steroids by masking ,* group as
esters or acetonides.
3(5 decrease in water solubility to increase palatability as in
chloramphenicol palmitate
6( Decrease ;I irritation (side effect) as in aspirin
0( Site specificity as in methyl dopa
-( Increased half(life and chemical stability as in cefamandole
acetate a stable prodrug while the parent cefamandole is
unstable solid dosage form. *etacillin is another prodrug (for
ampicillin ).