DRUG METABOLISM.pptx

DRUG METABBOLISM
22 June 2023 SIBI . K B . .PHARM 1
SIBIKULANTHAIVEL
Department of Pharmacology,
Nandha College of Pharmacy,
Erode-52

INTRODUCTION
PHARMACOKINETIC
What the drug did to the body ?
Pharmacokinetic is the quantitative study of the drug
movement in , through and out of the body. Intensity
effect is related to concentration of the drug at the
site of action , which depends on its pharmacokinetic
properties .
Drug ANY ROUTE Body ADME Elimination
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SIBI . K B . .PHARM

• Kinetics include the absorption of drug,
distribution of drug , metabolism of drug and
elimination of drug.
• ADSORPTION – passage of drug from the site
of administration.
• DISTRIBUTION – drug reaches the systemic
circulation , it gets distributed to other tissues.
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SIBI . K B . .PHARM
3

METABOLISM
It is the chemical conversion of one
chemical form of drug into another
chemical form. It includes enzymatically
driven chemical conversion , but some
of the drug may be chemically changed
by non- enzymatic process.
HYDROPHOBIC HYDRIPHILIC

OTHER NAMES
XENOBIOTIC
XENO- STRANGER/FOREIGN
BIOTIC- METABOLISM
DETOXIFICATION
TOXIC NON-TOXIC
BIOTRANSFORMATION

SITE OF METABOLISM
IN THE BODY – liver ,
small and large
intestine , lungs , skin ,
kidney , nasal mucosa
and brain.
liver is considered as the
major metabolic site foe
both drug and
endogenous substance.
intestine is the initial
metabolic site for the
drug .
Brain for glucose
metabolism.
Stomach for
carbohydrate, alcohol ,
lipid protein …..
Kidney for protein
,vitamin D, glutamine,
ammonia
carbohydrate…
Lungs for aerobic
metabolism

WHY LIVER IS MAJOR PATHWAY FOR
DRUG METABOLISM?
• The liver is present in between the circulatory
system and digestive system and it act as a
junction .
• Liver contain numerous microsomal enzyme
which are essential for the detoxification ,
mainly the enzyme CYP450.

FIRST PASS METABOLISM
• First pass metabolism / presystemic
metabolism / first pass effect.
• After oral administration many drugs are
absorbed from the small intestine transported
first via portal system to the liver, where they
undergo extensive metabolism before
reaching systemic circulation.
• First pass effect- liver 90%, git-9% and
circulation – 1%

CONCEPT OF METABOLISM
NATURE OF DRUG:
The lipid soluble drug will not get eliminated in
urine because , of the reabsorption in renal
tube and hence accumulate in the body , this
may cause toxic effect so, the drug to be
excreted in urine for this the drug must be
more polar ( water soluble )

DEFIENCE TO THE TOXIC
To make the drug more polar ,it under
goes metabolism through various
enzymatic system that changes the
parent compound to more water soluble
compound . Once the metabolite is
sufficiently water soluble it may
eliminated through urine and thus the
detoxification done.

WHY IT MUST TO BE POLAR ?
• To enhance the water solubility compare to
the parent compound.
• Less protein binding.
• Decrease the fatty tissue storage.
• Less permeability to cell membrane.
• Metabolite readily excreted through renal
system.

WHY DRUG METABOLISM IS
IMPORTANTAT ?
• Drugs are mostly lipid soluble , easy to cross
membrane , bind to plasma protein and
reabsorb from renal tubes
• Metabolism changes them to water soluble
and easily excretable products , also become
inactive or less active.

CONSEQUENCE OF METABOLISM
Through biotransformation generally inactivates
the drug, some drugs may be converted to
metabolites which are also active or more
active than the parent drug.
Biotransformation may also activate an inactive
drug . When the metabolite is active , the
duration of action gets prolonged . Prodrug is
an inactive drug which is get converted into
an active form in the body.

EXAMPLE
Cyclophosphamide is converted to acrolein
which cause bladder toxicity
Epoxide – shorting acting but highly reactive
molecule .
Epoxide include liver damage is countered to
large extent by glutathione.
Paracetamol is converted into N-acetyl Para –
benzoquinoneimine.

PARACETAMOL major pathway GLUCURONIDE
CYP450 minor pathway
N-ACETYL –P- BENZOQUINONEIMIN
(TOXIC METABOLITE)
NORMAL DOSE TREATMENT MORE TOXIC DOSE
GLUTATHIONE METHIONINE/ OXIDATION OF SH
CONJUCATION N-ACETYLCYSTINE(I.V)
PROTEIN BIND
TO TM
EXCRETE
TOXICITY CELL DEATH

IMPORTANCE OF METABOLISM
GENERAL
• To obtain chemical energy-ATP production.
• To synthesis complex molecule.
• To cover nutrient molecule into its precursor
form for future use.
• Detoxification.
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SIBI . K B . .PHARM

TERMIMNATION OF DRUG ACTION:
Conversion of drug to active metabolite to
inactive metabolite.
Parent compound inactive metabolite
Atropine tropic acid
Propranolol hydroxyl propranolol
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SIBI . K B . .PHARM

ACTIVATION OF PRODRUG:
The inactive drug get converted into active
drug is called pro drug.
INACTIVE DRUG ACTIVE METABOLITE
LEVODOPA DOPAMINE
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SIBI . K B . .PHARM

LESS TOXIC TO MORE TOXIC
In some cases the parent compound which are
metabolised which form the more toxic
substance . In liver the enzyme for
detoxification is secreted in defined quantity
so, in case of excess in take of drug make leads
to incomplete metabolism and the toxic
substance get accumulated in the liver and
cause hepatotoxicity .
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SIBI . K B . .PHARM

PHASES
OF
METABOLISM
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SIBI . K B . .PHARM

METABOLISM
PHASE-1Reaction involved
OXIDATION
REDUCTION
HYDROLYSIS
ACETYLATION
ENZYME INVOLVED
CYP450
FMO
ALDH
MAO
PHASE-2 reaction involved
Sulphate conjugation
Glucuronide conjugation
Glutathione conjugation
Amino acid conjugation
ENZYME INVOLVED
UDPGT
ST
NAT
MTAAC

PHASE-1 MEYTABOLISM
( NON- SYNTHETIC REACTION)
• Phase -1 reaction is also termed as non-synthetic
reaction . The purpose of this reaction is to introduce
the polar functional group into xenobiotic or drug
molecule to increase its water solubility so that it
can be easily excreted . It involves oxidation ,
reduction and hydrolysis. This result in activation ,
change /inactivation of drug .
• Phase -1 reaction introduce the functional grp live –
OH , -SH , -NH , -COOH and slightly increase the
hydrophilicity of drugs .
• The major of phase -1 reaction are generated by
common hydroxylting enzyme called CYP450.
22 June 2023 22
SIBI . K B . .PHARM

CYP450
• The cyp are superfamily of enzyme , that are involved
in the metabolism large number of dietary and
xenobiotic agents. Among the diverse reactions
carried out by mammalian cyp are O- dealkylation ,
N- methylation, aromatic hydroxylation , N- oxidation
, S-oxidation , deamination and dehalogenation. In
human there are 12 CYPs are important for
xenobiotic.
• Over 50 human P450 enzymes have been identified
and are classified according to their number of
shared amino acids.
22 June 2023 23
SIBI . K B . .PHARM

22 June 2023 24
SIBI . K B . .PHARM
CYP 450-CYCLE
CREATED BY SIBI.K
2NADPH+ RH + O2 NADP+ + ROH + H2O

MICROSOMAL & NON-MICROSOMAL
ENZYME
MICROSOMAL ENZYME- These are the enzyme
which metabolise the drug to make
detoxification process and the site of the
enzyme is endoplasmic reticulum in liver .
NON-MICROSOMAL ENZYME- These are the
enzyme which metabolise the drug to make
detoxification process and the site of the
enzyme is mitochondria , lysosome
These reaction catalysed by intestine microbial
flora.

OXIDATION
A most common phase -1 reaction involves
conversion of a C-H bond to C-OH . This
reaction sometimes coverts a
pharmacologically inactive compound to a
pharmacologically active one .
This reaction involves c cytochrome P450
monooxygenase , NADPH and oxygen .
Reaction result In proton enriched product .
OXIDATION- Addition of oxygen
22 June 2023 26
SIBI . K B . .PHARM

REACTION UNDER OXIDATION
MICROSOMALENZYME
 Aromatic hydroxylation
 Aliphatic hydroxylation
 N- dealkylation
 O- dealkylation
 S- dealkylation
 Oxidative deamination
 N- oxidation
 S- oxidation
NON-MICROSOMAL ENZYME
 Alcohol
dehydrogenation
Aldehyde oxidation
Amine oxidase
Aromatases

PHASE – II REACTION( SYNTHETIC REACTION)
The reaction generally involve covalent
attachment of small polar endogenous molecules
such as glucuronic acid , sulphate , glycine , etc to
either unchanged drugs or phase –I product
having suitable functional group –OH , -COOH , -
NH2 and -SH and form highly water soluble
conjugate which are readily excretable by the
kidney . Thus , these reaction is called conjugate
reaction . Since the outcome of such process are
generally product with increase molecular size ,
they are also called as synthetic reaction.

Quite often , a phase –I reaction may not yield a
metabolite that is sufficiently hydrophilic or
pharmacologically inert but conjugate reaction
generally result in product with total loss of
pharmacological activity and high polarity.
Hence , phase-II reaction are better known as
true detoxification reaction . Since these
reaction generally involve transfer of moieties
to the substrate to be conjugated , the
enzyme responsible are called as transferase.
Quite often , a phase –I reaction may not yield a
metabolite that is sufficiently hydrophilic or
pharmacologically inert but conjugate reaction
generally result in product with total loss of
pharmacological activity and high polarity.
Hence , phase-II reaction are better known as
true detoxification reaction . Since these
reaction generally involve transfer of moieties
to the substrate to be conjugated , the
enzyme responsible are called as transferase.

WHY PHASE –II REACTION IS TRUE
DETOXIFICATION REACTION ?
• They are absolutely free from pharmacological
activity .
• They are highly polar and easily excreted
either urine or bile .
• Tissue reactive and carcinogenic metabolites
formed as a result of phase –I reaction are
rendered harmless by conjugation with
moieties such as glutathione.

PHASE –II REACTION AND THEIR CHARACTERISTIC
CONJUGATION
REACTION
CONGUGATING
AGENT
CONGUCATING
AGENT
TRANSFERRING
ENZYME
ACTIVATED
INTERMEDIATE
FUNCTIONAL GRP.
COMBAINED WITH
GLUCURONIDATION GLUCURONIC ACID UDP –GLUCURONYL
TRANSFERASE
UDPGA -OH , -COOH , -NH2 ,
-SH
SULPHATION
AMINO ACID
CONJUGATION
SULPHATE
GLYCINE
SULPHOTRANSFERASE
ACYL TRANSFERASE
PAPS
ACYL Co A
-OH , -NH2
-COOH , -NH2
GLUTATHIONE GLUTATHIONE GLUTHAIONE – S –
TRANSFERASE _
ALKYL HALIDE ,
ALKYL NITRATES ,
EPOXIDE ,
LACTONES
ACETYLATION ACETYL Co A N-ACETYL
TRANSFERASE
ACETYL Co A -NH2 , -SO2 NH2 ,
HYDRAZINES
METHYLATION L-METHIONINE METHYL
TRANSFERASE
S-ADENOSYL
METHIONONE
-OH , -NH2 , -SH

GLUCURONIDATION
(CONGUCATION WITH GLUCURONIC ACID )
It is important reaction for several following reasons.
• Readily available source of conjugation moiety , D-
GLUCURONIC ACID which is derived from D-GLUCOSE
• Several functional group live ALCOHOL , ACID ,
AMINES can combine easily with D-GLUCURONIC
ACID.
• Quantitatively , conjugation with D-GLUCURONIC
ACID occurs to high degree.
• All mammals have the common ability to produce
glucuronides.

• The free carboxyl function of glucuronic acid
has a pKa in the range 3.5 to 4.0 and hence
ionisable at both plasma and urine pH there
by gently increasing the water solubility of the
conjugated substrate.
• The glucuronidation enzyme are close
associated with the microsomal mixed
function oxidase , the major phase –I drug
metabolism enzyme system , thus a rapid
conjugation of phase-I metabolite is possible
• UDPGA is produced in process related to
glycogen synthesis and there is no deficient.

α –D –GLUCOSE -1-PHOSPHATE UDPG
UDPG DEHYDROGENASE
UDPGA +ROH
UDP-GLUCURONYL TRANSFERASE
β-GLUCURONIDE CONJUGATE
EXCRETED IN URINE

Oxygen or O-Glucuronides:
Xenobiotics with hydroxyl and/or carboxyl functions form O-
glucuronides.
1. Hydroxyl Compounds:
These form ether glucuronides. Several examples of such
compounds are given below
 Aliphatic alcohols e.g. chloramphenicol, trichloroethanol
 Alicyclic alcohols e.g. hydroxylated hexobarbital
 Arenols (phenols) e.g. morphine, paracetamol
 Benzylic alcohols e.g. methyl phenyl carbinol
 Enols e.g. 4-hydroxy coumarin
 N-hydroxyl amines e.g. N-hydroxyl dapsone
 N-hydroxyl amides e.g. N-hydroxy-2-acetyl aminofluorine

Carboxyl Compounds :
These form ester glucuronides.
Aryl acids e.g. salicylic acid
 Arylalkyl acids e.g. fenoprofen
Nitrogen or N-Glucuronides:
Xenobiotics with amine, amide and sulphonamide
functions form N-glucuronides.
 Aliphatic 2o amines e.g. desipramine
 Aliphatic 3o amines e.g. tripelennamine
 Nonaromatic 3o heterocyclic amines
e.g.cyproheptadiene
 Amides e.g. meprobamate

Sulphur or S-Glucuronides :
Thiols (SH) form thioether glucuronides e.g.
thiophenol. Carbon or C-Glucuronides
Xenobiotics with nucleophilic carbon atoms
such as phenylbutazone form C-glucuronides.
Certain endogenous compounds such as
steroids, bilirubin, catechols and thyroxine
also form glucuronides.

SULPHATE CONJUGATION
(CONJUGATION WITH SULPHATE MOITEY)
Sulphation is similar to glucuronidation but it is
catalysed by nonmicrosomal enzymes and occurs
less commonly as the moiety that transfers
sulphate to the substrate is easily depleted. This
process is thus, easily saturable in comparison to
glucuronidation.
Sulphation is dominant at low substrate
concentration, whereas Glucuronidation is
dominant at high substrate concentration.

STEPS INVOLVED
Synthesis of an activated
coenzyme3phosphoadenosine-5'-
phosphosulphate (PAPS) which acts as a donor of
sulphate to the substrate. This also occurs in two
steps — (a) An initial interaction between the
sulphate and the adenosine triphosphate (ATP) to
yield adenosine-5'-phosphosulphate (APS),
followed by (b) Activation of APS to PAPS.
Transfer of sulphate group from PAPS to the
substrate RXH in presence of enzyme
sulphotransferase (sulphokinase) and subsequent
liberation of 3'-phosphoadenosine-5'phosphate
(PAP).

SULPHATE ION
ATP – SULFURYLASE
ADENOSINE – 5 PHOSPHO SULPHATE
PHOSPHOKINASE
PAPS +RXH
PAPS
SUPLHATE CONJUGATE

Functional groups capable of forming sulphate
conjugates include phenols, alcohols, arylamines,
N- hydroxylamines and N- hydroxyamides .
The reaction product is a sulphate ester, also called
as ethereal sulphate.
Phenols e.g. paracetamol, salbutamol
Alcohols e.g. aliphatic alcohols C-1 to C-5
Arylamines e.g. aniline.
Sulphoconjugates can be tissue reactive,
e.g. the O-sulphate conjugate of N-
hydroxyphenacetin covalently binds to hepatic
and renal tissues.
Endogenous substances can also undergo
sulphation, e.g. steroids, biologic amines, etc.

CONJUGATION OF AMINO ACID
This reaction also occurs to a limited extent because
of limited availability of amino acids.
The reaction occurs in two steps:
Activation of carboxylic acid drug substrate with
ATP and coenzyme A (CoA) to form an acyl CoA
intermediate. Thus, the reaction is a contrast of
glucuronidation and sulphation where the donor
coenzyme is activated and not the substrate.
Acylation of the -amino acid by the acyl CoA in
presence of enzyme N-acyl transferase.

RCOOH (ACID) + ATP
ACYL SYNTHETASE
RCOAMP + H2O+PPi
ACYL TRANSFERASE
RCOSCOA + AMP
H2NRCOOH (SUBSTRATE)
N – ACYL TRANSFERASE
RCONHRCOOH(AMIDE) + COASH

Conjugation occurs commonly with glycine.
Glutamine conjugation occurs to a lesser
extent. Conjugation with other amino acids
like aspartic acid, serine and taurine is still
uncommon. The substrate is generally an acid
(aromatic in particular) and the reaction
product is an amide .
 Aliphatic acids e.g. isopropoxy-acetic acid
Alicyclic acids e.g. cholic acid
 Aryl acids e.g. salicylic acid
 Aryl acetic acids e.g. phenylacetic acid
Heterocyclic aryl acids e.g. nicotinic acid.

Amino acid conjugation occurs extensively in the
liver mitochondria and thus the reaction can
be used to estimate hepatic function. The
diagnostic marker used is benzoic acid which
on conjugation with glycine yields hippuric
acid.
Hippuric acid is rapidly excreted in urine. Thus,
the rate and extent of urinary excretion of
hippuric acid following oral or I.V.
administration of benzoic acid indicates
functioning of liver. A decreased output
indicates hepatic disorder.

GLUTATHIONE CONJUGATION
Glutathione ( -glutamyl cysteinyl glycine or GSH)
is a tripeptide with a strongly nucleophilic
character due to the presence of a -SH (thiol)
group in its structure.

• Thus, it has great affinity for electrophilic
substrates, a number of which are potentially
toxic compounds. It is important to note that
a highly electrophilic metabolite has a
tendency to react with tissue nucleophilic
groups such as -OH, -NH2 and -SH and
precipitate toxicities
• such as tissue necrosis, carcinogenesis,
mutagenesis, teratogenesis, etc. Conjugation
with glutathione protects the tissue from such
reactive moieties and thus, the reaction is an
important detoxication route

GLUTATHIONE CONJUGATION
OCCURS BY EITHER NUCLEOPHILIC SUBSTITUTION / ADDITION

ACETYLATION
Acetylation is an important metabolic pathway
for drugs containing primary amino groups.
Alcohols (e.g. choline) and thiols (e.g. CoASH)
also undergo acetylation but only the
endogenous ones.

Primary aliphatic amines e.g. histamine,
mescaline.
Primary aromatic amines e.g. procainamide,
PAS, PABA, dapsone.
 Sulphonamides e.g. sulphanilamide,
sulphapyridine.
Hydrazines / hydrazides e.g. hydralazine,
isoniazid, phenelzine.
Acetylation may sometimes lead to toxic
products, e.g. acetyl derivatives of some
sulphonamides (cause renal toxicity due to
decreased water solubility of the metabolites
formed) and reactive arylacetamides.

METHYLATION
Methylation can be considered as intermediate of phase I
and phase II reactions. It can be called as a phase I
reaction as it is reverse of demethylation reaction and
can be classed as a phase II reaction because of its
mechanism. Methylation of substrates proceeds in
two steps:
Synthesis of an activated coenzyme S- adenosyl
methionine (SAM), the donor of methyl group, from L-
methionine and ATP.
Transfer of the methyl group from SAM to the substrate
in presence of nonmicrosomal enzyme methyl
transferase.

Important methyl transferases that catalyse
methylation of xenobiotics are catechol-
Omethyl transferase (COMT), phenyl-O-methyl
transferase (POMT), phenyl ethanolamine-N-
methyl transferase (PNMT), nonspecific
transferases, etc.

Examples of substrates undergoing methylation
are:
• O-Methylation Phenols e.g. morphine
• Catechols e.g. -methyl dopa, L-DOPA,
isoprenaline
• N-Methylation Primary aliphatic amines e.g.
nor ephedrine
• Secondary alicyclic amines e.g. nor morphine
• Aromatic heterocycles e.g. nicotine, histamine
• S-Methylation Thiols e.g. propylthiouracil, 6-
mercaptopurine

FACTORS AFFECTING XENOBIOTICS
CHEMICAL FACTORS
ENZYME INDUCTION
ENZYME INHIBITION
PHYSICAL FACTORS
OTHER FACTORS
Age
Diet
Sex difference
Genetic difference
Species difference
Altered physiological

ENZYME INDUCTION
The phenomenon of increased drug metabolized
ability of the enzyme by the several drugs and the
chemicals is called as enzyme induction .
Some drugs induce their own mechanism are called
self inducers . Induction may result from
transcriptional activation or enzyme stabilization
. A number of drugs have the ability can cause an
increasing in the liver enzyme activity over time .
Many drugs have the ability to stimulate the
activity of CTY450 isforms .

Mechanism of enzyme induction
 Increased in synthesis of CTP450
 Increased in stability of enzyme
 Increase in both total and microsomal protein content.
 Increase both liver size and liver blood flow .
ENVIRONMENT CHEMICALS ALSO ALTER THE ACTIVITY OF
CYP450.
 Cigarette smoking
 Xanthine and flavones food
 Polycyclic aromatic hydrocarbons
 Halogenated hydrocarbons in insecticides
 Food additives

ENZYME INHIBITION
The phenomenon of dreasing in the drug metabolizing
ability of an enzyme by several drugs and chemicals is
called an enzyme inhibition .
The process of inhibition is of two steps
Direct inhibition
Competitive
Non competitive
Product inhibition
Indirect inhibition
Repression
Altered physiology.

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