1

2
DRUG BIO1RANSIORMA1ION DRUG BIO1RANSIORMA1ION
(ML1ABOLISM) (ML1ABOLISM)
3
Drug metabolism Drug metabolism is the is the biochemical biochemical
modiication o modiication o pharmaceutical substances pharmaceutical substances by by
liing liing organisms organisms, usually through specialized , usually through specialized
enzymatic enzymatic systems. systems.
rug metabolism oten conerts rug metabolism oten conerts lipophilic lipophilic
chemical compounds chemical compounds into more readily into more readily excreted excreted
polar polar products. products.
4
rug rug metabolism can result in metabolism can result in toxication toxication or or
detoxication detoxication -- the actiation or deactiation o the the actiation or deactiation o the
chemical. \hile both may occur, the major metabolites chemical. \hile both may occur, the major metabolites
o most drugs are detoxication products. o most drugs are detoxication products.
rugs are almost all rugs are almost all xenobiotics xenobiotics. ,Synthetic, Other . ,Synthetic, Other
commonly used commonly used organic chemicals organic chemicals are also xenobiotics, are also xenobiotics,
and are metabolized by the same and are metabolized by the same enzymes enzymes as drugs. as drugs.
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DEFINITION DEFINITION - -
BIOTRANSFORMATION BIOTRANSFORMATION
BIO derived from GRLLK Word BIOS meaning BIO derived from GRLLK Word BIOS meaning
life life
1ransformation meaning alteration / change 1ransformation meaning alteration / change
Chemical alteration that a drug molecule Chemical alteration that a drug molecule
undergoes in a living organism with consequent undergoes in a living organism with consequent
change in its solubility & activity change in its solubility & activity
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BIOTRANSFORMATION.. BIOTRANSFORMATION..
Objectives Objectives
Inactivation of Drugs Inactivation of Drugs
Llimination of Drugs Llimination of Drugs
Activation of Pro Activation of Pro- -drugs drugs
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Inactivation of Drugs Inactivation of Drugs
ostly drugs are inactiated so as to be biologically ostly drugs are inactiated so as to be biologically
ineectie ineectie
Lxceptions Lxceptions
Some drugs may be more actie, potent, toxic Some drugs may be more actie, potent, toxic
iazepam conerted into Oxzepam iazepam conerted into Oxzepam
Parathion conerted into Paraoxon Parathion conerted into Paraoxon -- -- toxic toxic
Objectives Objectives- -
BIOTRANSFORMATION.. BIOTRANSFORMATION..
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Llimination of Drugs Llimination of Drugs
onersion o lipid soluble , non onersion o lipid soluble , non--polar compounds in to polar compounds in to
water soluble,lipid insoluble ,polar metabolites water soluble,lipid insoluble ,polar metabolites
not reabsorbed rom Renal 1ubules ater iltration at glomerulus not reabsorbed rom Renal 1ubules ater iltration at glomerulus
excretion in urine and elimination rom body excretion in urine and elimination rom body
Lxception: Lxception: some drugs may be made less water soluble some drugs may be made less water soluble
Diazepam converted in to Desmethyl Diazepam Diazepam converted in to Desmethyl Diazepam
Objectives Objectives- -
BIOTRANSFORMATION.. BIOTRANSFORMATION..
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Activation of Pro Activation of Pro- -drugs drugs
Pro Pro--drug is an inactie precursor o a drug that has drug is an inactie precursor o a drug that has
to be actiated by biotransormation ater to be actiated by biotransormation ater
administration to the patient administration to the patient
Bac Bac-- ampicillin is conerted to ampicillin ampicillin is conerted to ampicillin
Objectives Objectives- -
BIOTRANSFORMATION.. BIOTRANSFORMATION..
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PRODRUG PRODRUG
Cortisone Cortisone
Valciclovir Valciclovir
Prednisone Prednisone
1al 1al Ampicillin Ampicillin
Piv Piv
Bac Bac
Chlorazepate Chlorazepate
Atracurium Atracurium
AC1IVL DRUG AC1IVL DRUG
Hydrocortisone Hydrocortisone
Acyclovir Acyclovir
Prednisolone Prednisolone
Ampicillin Ampicillin

Desmethyl Diazepam Desmethyl Diazepam

Laudanosine & Quaternary acid Laudanosine & Quaternary acid
Objectives Objectives- -
BIOTRANSFORMATION.. BIOTRANSFORMATION..
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ADVANTAGES OF ADMINISTRATION OF A ADVANTAGES OF ADMINISTRATION OF A
PRO PRO- -DRUG DRUG
1o 1o make make a a drug drug tasteless tasteless and and more more stable stable ee..gg.. Propoxyphene Propoxyphene
hydrocloride hydrocloride ,bitter ,bitter and and unstable, unstable, Propoxyphene Propoxyphene Naphsylate Naphsylate
,tasteless ,tasteless & & stable, stable,..
1o 1o make make the the drug drug more more palatable palatable ee..gg.. hloramphenicol hloramphenicol Palmitate Palmitate is is
gien gien instead instead o o hloramphenicol hloramphenicol..
1o 1o improe improe the the rate rate o o absorption absorption o o a a drug drug ee..gg..
1al 1al -- Ampicillin, Ampicillin, Pi Pi -- Ampicillin Ampicillin & & Bac Bac -- Ampicillin Ampicillin are are gien gien instead instead
o o Ampicillin Ampicillin..
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1o 1o improe improe the the Bioaailability Bioaailability o o a a drug drug ee..gg.. Valcicloir Valcicloir ,, prodrug prodrug o o
Acycloir Acycloir
1o reduce the toxicity o a drug e.g. 1al 1o reduce the toxicity o a drug e.g. 1al--ampicillin, Pi ampicillin, Pi -- ampicillin & ampicillin &
Bac Bac--ampicillin are gien instead o Ampicillin. ampicillin are gien instead o Ampicillin.
1o 1o increase increase the the concentration concentration o o a a drug drug at at its its site site o o action action ee..gg..
Leodopa Leodopa in in place place o o opamine opamine..
1o 1o increase increase the the duration duration o o action action o o a a drug drug ee..gg.. Phenothiazine Phenothiazine
luphenazine luphenazine ,ester ,ester deriaties deriaties like like luphenazine luphenazine enanthate, enanthate,
luphenazine luphenazine decanoate, decanoate,..
ADVANTAGES OF ADMINISTRATION OF A PRO ADVANTAGES OF ADMINISTRATION OF A PRO- -DRUG. DRUG.
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SITES SITES DRUG BIOTRANSFORMATION DRUG BIOTRANSFORMATION
Liver Liver - - main site main site
Lungs, Kidneys, Intestine, plasma, Placenta (term), Lungs, Kidneys, Intestine, plasma, Placenta (term),
Adrenals, Skin, Brain. Adrenals, Skin, Brain.
Liver Liver Meperidine, Pentazocine, Morphine, Nitroglycerine, Meperidine, Pentazocine, Morphine, Nitroglycerine,
Lignocaine, Propranolol,Paracetamol, Prazosin Lignocaine, Propranolol,Paracetamol, Prazosin
GIT GIT Insulin, Catecholamines, Clonazepam, Chlorpromazine, Insulin, Catecholamines, Clonazepam, Chlorpromazine,
Tyramine & Salbutamol Tyramine & Salbutamol
Lungs Lungs Prostanoids (prostaglandins & thromboxanes) Prostanoids (prostaglandins & thromboxanes)
Plasma Plasma Suxamethonium (succinylcholine), Procaine, Propanidid, Suxamethonium (succinylcholine), Procaine, Propanidid,
Aspirin, Clofibrate Aspirin, Clofibrate
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FIRST FIRST- -PASS EFFECT/METABOLISM OR PASS EFFECT/METABOLISM OR
PRESYSTEMIC METABOLISM PRESYSTEMIC METABOLISM
Metabolism / inactivation of drug before it reaches systemic Metabolism / inactivation of drug before it reaches systemic
circulation circulation
Drugs undergoing extensive first Drugs undergoing extensive first- -pass effect pass effect
Lignocaine Lignocaine
Nitroglycerine Nitroglycerine
Insulin Insulin
Sympathomimetic catecholamines Sympathomimetic catecholamines
Morphine Morphine
Meperidine Meperidine
Pentazocine Pentazocine
Chlorpromazine Chlorpromazine
Clonazepam Clonazepam
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16
Non Non- -enzymutic enzymutic Enzymutic Enzymutic
MicrosomuI MicrosomuI Non Non- -microsomuI microsomuI
TYPES TYPES - BIOTRANSFORMATION
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a. a. Phase Phase- -I (Non I (Non- -synthetic) synthetic)
b. b. Phase Phase- -II (Synthetic/Conjugation) II (Synthetic/Conjugation)
Reactions of Enzymatic Biotransformation Reactions of Enzymatic Biotransformation
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Pattern oI Reactions Pattern oI Reactions
Drug Drug Phase Phase- -I I Phase Phase- -II II
Exception Exception
Phase Phase- -II II may may precede precede phase phase- -I I reaction reaction ee..gg.. Isoniazid Isoniazid --- ---
Phase Phase- -II II reaction reaction (acetylation) (acetylation) take take place place Iirst Iirst and and is is
Iollowed Iollowed by by phase phase- -I I reaction reaction (Hydrolysis) (Hydrolysis)
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INH
N-Acetyl INH
Isonicotinic acid Acetyl Hydrazine
Hepatotoxicity
Acetylation
Phase II reaction
Hydrolysis
Phase I reaction
Acetylation oI Proteins
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21
Phase Phase - -I Reactions (Non I Reactions (Non - - synthetic) synthetic)
Main Phase Main Phase- -I Reactions I Reactions
I. Oxidation I. Oxidation
II. Reduction II. Reduction
III. Hydrolysis III. Hydrolysis
Reactions oI Enzymatic BiotransIormation Reactions oI Enzymatic BiotransIormation
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EIIects oI Phase EIIects oI Phase- -I Reactions on Drug I Reactions on Drug
Generally parent drug is converted to a more polar / Generally parent drug is converted to a more polar /
less lipid soluble metabolite . less lipid soluble metabolite .
OIten the metabolites are inactive. OIten the metabolites are inactive.
Sometime activity is only modiIied or even Sometime activity is only modiIied or even
enhanced enhanced
II metabolite is suIIiciently polar, it may be excreted II metabolite is suIIiciently polar, it may be excreted
via kidney in urine. via kidney in urine.
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Phase Phase - -I Reactions (Non I Reactions (Non - - synthetic) synthetic)
I. Oxidation I. Oxidation
Most important drug metabolizing reactions Most important drug metabolizing reactions
Involves Involves
Addition oI oxygen/ Addition oI oxygen/ - -vely charged radical. vely charged radical.
Removal oI hydrogen/ vely charged radical. Removal oI hydrogen/ vely charged radical.
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I. Oxidation I. Oxidation
Enzymes: Enzymes:- - Two types Two types
a. a. Microsomal/Mixed function oxidases system Microsomal/Mixed function oxidases system
located in Smooth Endoplasmic Reticulum in liver & other located in Smooth Endoplasmic Reticulum in liver & other
tissues. tissues.
b. b. Non Non- -Microsomal Microsomal located in located in
Cytosol Cytosol
Mitochondria Mitochondria
Lysosomes Lysosomes
Nuclear membrane Nuclear membrane
Plasma membrane Plasma membrane
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Mixed Function Oxidases (MFOs) OR
Monooxygenases
Two key enzymes
Cytochrome P450-- Hemoprotein
NADPH-Cytochrome P450 reductase ------Flavoprotein
Consists oI 1 mol each oI Ilavin mononucleotide (FMN) &
Ilavin adenine dinucleotide (FAD).
The activity of these enzymes requires:
NADPH (Nicotinamide Adenine Dinucleotide Phosphate)
reducing agent.
Molecular oxygen
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Oxidative Oxidative cycle cycle
Step 1: Step 1: Oxidized (Fe Oxidized (Fe
3 3
) P450 combines with a drug substrate ) P450 combines with a drug substrate
to Iorm a binary complex. to Iorm a binary complex.
Step 2: Step 2: NADPH donates an electron to the Ilavoprotein P450 NADPH donates an electron to the Ilavoprotein P450
reductase, which in turn reduces the oxidized P450 drug reductase, which in turn reduces the oxidized P450 drug
complex. complex.
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Step 3: Step 3: A second electron is introduced rom NAPl ia the A second electron is introduced rom NAPl ia the
same P450 reductase, which reduces molecular oxygen to an same P450 reductase, which reduces molecular oxygen to an
activated oxygen activated oxygen P4S0 substrate complex P4S0 substrate complex
Step 4: Step 4: 1he complex transers actiated oxygen to the drug 1he complex transers actiated oxygen to the drug
substrate to orm the oxidized product. substrate to orm the oxidized product.
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MICROSOMAL LNZYMLS MICROSOMAL LNZYMLS
RUG BIO1RANSORA1ION RUG BIO1RANSORA1ION
0

0

Chain of Reactions:-
WOxidized (Fe
3
)P450 Drug
W Reduced (Fe
2
) P450 Drug Complex
-Reduced (Fe 2+) P4S0 - Drug Complex +O
2
Activated O
2
- (Fe
2
) P450 Drug Complex
WOxidized drug metabolite H
2
O Oxidized (Fe
3
)P450 Regenerated & Recycled
O
2
(NFOS)
e
-
2 x H ions, e
-
2 x H ions, e
-
e
Cytochrome P4S0 cycle in drug oxidation
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P450 Cytochrome Isoenzymes: P450 Cytochrome Isoenzymes: ( (CYP) CYP)
( (CYP) CYP) P450 has several isoIorms (about 50), grouped into: P450 has several isoIorms (about 50), grouped into:
Families Families designated by numerals (1,2,3,.) designated by numerals (1,2,3,.)
Sub Sub- -Iamilies Iamilies designated by capital letters (A,B,C..) designated by capital letters (A,B,C..)
Individual Isoenzymes are again allotted numerals Individual Isoenzymes are again allotted numerals (1,2,3,.) (1,2,3,.)
CYP 1A2 , CYP 3A4 , CYP 2A6 CYP 1A2 , CYP 3A4 , CYP 2A6
CYP 2C9 CYP 2C9
CYP 2D6 CYP 2D6
CYP 2E1 CYP 2E1
CYP CYP3A4 Metabolises over 50 oI drugs . 3A4 Metabolises over 50 oI drugs .
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a. a. Is under genetic control, as in case oI CYP2C19 Is under genetic control, as in case oI CYP2C19
and CYP2D6. and CYP2D6.
b. b. Is inducible. Is inducible.
c. c. Is inhibitable. Is inhibitable.
d. d. Gradually & slowly evolved as a result oI Gradually & slowly evolved as a result oI
exposure to toxins in plants and environment, as a exposure to toxins in plants and environment, as a
saIety & protective mechanism Ior human saIety & protective mechanism Ior human beings & beings &
animals. animals.
e. e. Its activity is modiIied by various Iactors. (age, Its activity is modiIied by various Iactors. (age,
sex, species, sex, species, altitude, climate, etc.) altitude, climate, etc.)
Features Features
Mixed Mixed Function Oxidase Enzyme System Function Oxidase Enzyme System
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Reaction class Reaction class Drug Substrates Drug Substrates
Microsomal Oxidations
Hydroxylation Hydroxylation Phenobarbitone, Propranolol Phenobarbitone, Propranolol
Phenytoin , Amphetamines Phenytoin , Amphetamines
Epoxidation Epoxidation Aldrin Aldrin
N N- - Dealkylation Dealkylation Morphine, CaIIeine, Morphine, CaIIeine,
Theophylline Theophylline
O O- - Dealkylation Dealkylation Codeine Codeine
N N- -oxidation oxidation Acetaminophen , Nicotine Acetaminophen , Nicotine
S S- -Oxidation Oxidation Chlorpromazine, Cimetidine Chlorpromazine, Cimetidine
Deamination Deamination Amphetamine, Diazepam Amphetamine, Diazepam
DesulIuration DesulIuration Thiopental Thiopental
Dechlorination Dechlorination Carbon tetrachloride Carbon tetrachloride
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Reaction class Reaction class Drug Substrates Drug Substrates
Non-Microsomal Oxidations
Flavin monooxygenase Flavin monooxygenase Chlorpromazine Chlorpromazine
Amine oxidases Amine oxidases Phenylethylamine, Phenylethylamine,
Epinephrine Epinephrine
Dehydrogenation Dehydrogenation Ethanol , Chloral hydrate Ethanol , Chloral hydrate
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II. Reductions II. Reductions
Converse of oxidation Converse of oxidation
It involves It involves
Addition oI hydrogen / vely charged radical. Addition oI hydrogen / vely charged radical.
Removal oI oxygen / Removal oI oxygen / - -vely charged radical vely charged radical
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Reductions Reductions
Azo reductions Azo reductions Prontosil Prontosil
Nitro reductions Nitro reductions Chloramphenicol, Chloramphenicol,
Clonazepam ,Dantrolene. Clonazepam ,Dantrolene.
Carbonyl reductions Carbonyl reductions Methadone, Naloxone Methadone, Naloxone
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III. Hydrolysis III. Hydrolysis
Cleavage oI drug molecule by taking up a molecule oI Cleavage oI drug molecule by taking up a molecule oI
water. water.
Esterase Esterase
Ester and water Ester and water acid and alcohol acid and alcohol
Hydrolysis Hydrolysis
Esters Esters Procaine, Acetylcholine , Procaine, Acetylcholine ,
Suxamethonium Suxamethonium
Amides Amides Procainamide Procainamide
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Phase Phase - -II Reactions (Synthetic) II Reactions (Synthetic)
Conjugation Conjugation -- -- main Phase main Phase- -II Reaction II Reaction
Functionalization Functionalization --- ---Certain groups are Certain groups are
introduced/unmasked in the drug`s chemical introduced/unmasked in the drug`s chemical
structure, e.g. Sulphydryl, Hydroxyl, structure, e.g. Sulphydryl, Hydroxyl,
Carboxyl, Amino groups. They are important Carboxyl, Amino groups. They are important
Ior Phase Ior Phase- -II reactions II reactions
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Types oI conjugation Types oI conjugation
Glucuronoid conjugation Glucuronoid conjugation
Glutathione conjugation Glutathione conjugation
Glycine conjugation Glycine conjugation
SulIate conjugation SulIate conjugation
Water conjugation Water conjugation
N N- -Acetylation Acetylation
Methylation Methylation
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39
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PHASE PHASE - -II REACTIONS II REACTIONS
Type of Type of
Conjugation Conjugation
Endogenous Endogenous
Reactant Reactant
Examples Examples
Glucuronidation Glucuronidation UDP UDP- -glucuronic acid glucuronic acid Morphine, acetaminohpen ,Diazepam Morphine, acetaminohpen ,Diazepam
,Digoxin ,Digoxin
Acetylation Acetylation Acetyl Acetyl CoA CoA SulIonamides, isoniazid , Clonazepam SulIonamides, isoniazid , Clonazepam
,Dapsone ,Dapsone
Glutathione Glutathione
conjugation conjugation
Glutathione Glutathione Ethacrynic acid, paracetamol Ethacrynic acid, paracetamol
Glycine Glycine
conjugation conjugation
Glycine Glycine Salicylic acid, Nicotinic acid Salicylic acid, Nicotinic acid
SulIate SulIate
conjugation conjugation
Phosphoadenosyl Phosphoadenosyl- -
PhosphosulIate PhosphosulIate
Acetaminophen, methyldopa Acetaminophen, methyldopa
Methylation Methylation
S S- -Adenosylmethionine Adenosylmethionine
Dopamine, epinephrine ,Histamine , Dopamine, epinephrine ,Histamine ,
Nor epinephrine Nor epinephrine
Water Water
Conjugation Conjugation
Water Water
Leukotrine Leukotrine
A4 A4
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EIIects oI Phase EIIects oI Phase II Reactions II Reactions
Lipid solubility totally converted in to water Lipid solubility totally converted in to water
solubility solubility excreted through kidney. excreted through kidney.
Drugs are generally inactivated. Drugs are generally inactivated.
Exceptions: Exceptions:
Sometimes drug activity is increased. Sometimes drug activity is increased.
a. Minoxidil a. Minoxidil Minoxidil sulphate (active metabolite). Minoxidil sulphate (active metabolite).
b. Morphine b. Morphine Morphine 6 Morphine 6- -Glucuronide (active metabolite) Glucuronide (active metabolite)
Sometimes highly toxic metabolites are formed. Sometimes highly toxic metabolites are formed.
Paracetamol Paracetamol N N- - acetylebenzoiminoquinone acetylebenzoiminoquinone
(in high doses ) (toxic metabolite) (in high doses ) (toxic metabolite)
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Non Non- -enzymatic BiotransIormation enzymatic BiotransIormation
OR OR
HoIIman Elimination HoIIman Elimination
A A form form of of biotransformation biotransformation in in which which there there is is
spontaneous spontaneous alteration alteration in in chemical chemical structure structure of of aa
drug drug as as aa result result of of change change of of the the pH pH of of body body fluids, fluids,
enzymes enzymes do do not not participate participate
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Examples Examples
Non Non- -enzymatic BiotransIormation enzymatic BiotransIormation
Atracurium Atracurium Laudanosine & Quaternary acid Laudanosine & Quaternary acid
Hexamine Hexamine (at acidic pH oI urine) (at acidic pH oI urine) Formaldehyde Formaldehyde
Chlorazepate Chlorazepate Desmethyl Diazepam Desmethyl Diazepam
(at acidic pH in the stomach) (at acidic pH in the stomach)
Mustine HCl Mustine HCl (Mechlorethamine) (Mechlorethamine) Ethyleneimonium Ethyleneimonium
44
FACTORS MODIFYING FACTORS MODIFYING
BIOTRANSFORMATION BIOTRANSFORMATION
They produce individual variation in drug They produce individual variation in drug
metabolism metabolism
Genetic factors Genetic factors
Non Non- -genetic factors genetic factors
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Non Non- -genetic Iactors genetic Iactors
Drug Drug - -Drug Interactions: Drug Interactions: Enzyme Induction, Enzyme Induction,
Enzyme Inhibition Enzyme Inhibition
Age & sex Age & sex
Diet & Environmental Factors Diet & Environmental Factors: : Smoking, Smoking,
Alcoholism, Exposure to pesticides Alcoholism, Exposure to pesticides
Interactions between Drugs & Endogenous Interactions between Drugs & Endogenous
compounds . compounds .
Pathological states of liver, CVS, lungs, Pathological states of liver, CVS, lungs,
endocrines. endocrines.
Nutritional status: starvation, malnutrition Nutritional status: starvation, malnutrition
46
Enzyme Induction Enzyme Induction
Definition: Definition:
It is It is increased activity of CYP450 enzymes increased activity of CYP450 enzymes by certain by certain
drugs or chemicals, due to increased synthesis/ decreased drugs or chemicals, due to increased synthesis/ decreased
degradation oI selected enzymes, degradation oI selected enzymes, accelerating the substrate accelerating the substrate
metabolism, decreasing plasma levels & leading to metabolism, decreasing plasma levels & leading to
therapeutic Iailure. therapeutic Iailure.
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Enzyme Induction. Enzyme Induction.
Example Example
Two drugs given together & one is enzyme inducer Two drugs given together & one is enzyme inducer--- ---
- - Drug Interactions Drug Interactions
Warfarin (oral anticoagulant) & Warfarin (oral anticoagulant) &
phenobarbital phenobarbital
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Enzyme inducers Enzyme inducers
The drugs producing enzyme induction are known The drugs producing enzyme induction are known
as Enzyme inducers as Enzyme inducers
These include: These include:
Various drugs: Various drugs: Phenobarbital, phenytoin, RiIampin, Phenobarbital, phenytoin, RiIampin,
Carbamazepine, Dexamethasone Carbamazepine, Dexamethasone
Chemicals : Chemicals : Insecticides Insecticides and and Environmental pollutants: Environmental pollutants:
Tobacco smoke , Charcoal Tobacco smoke , Charcoal- -broiled meat can induce CYP1A broiled meat can induce CYP1A
enzymes. They contain Benzo enzymes. They contain Benzo --( ( pyrene & other aromatic pyrene & other aromatic
hydrocarbons. hydrocarbons.
49
Enzyme Inducers Enzyme Inducers
Phenobarbitone Phenobarbitone CYP2B1 CYP2B1
Phenytoin Carbamazepine & Phenytoin Carbamazepine &
other anticonvulsants, other anticonvulsants,
Glucocorticoids, Glucocorticoids, Some other Some other
Steroids Macrolides Steroids Macrolides
CYP3A4/5 CYP3A4/5
Benzo Benzo --( pyrene in tobacco ( pyrene in tobacco
smoke. smoke.
CYP1A1 CYP1A1
Ch. Alcoholism, Isoniazid Ch. Alcoholism, Isoniazid CYP2E1 CYP2E1
Rifampin, Rifampin, Dexamethasone Dexamethasone CYP3A in Liver & Intestinal CYP3A in Liver & Intestinal
mucosa mucosa
Clofibrate Clofibrate CYP4A CYP4A
Carbamazepine Carbamazepine Autoinduction Autoinduction
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Consequences oI Microsomal Enzyme Induction Consequences oI Microsomal Enzyme Induction
1. Therapeutic failure. Due to decreased plasma 1. Therapeutic failure. Due to decreased plasma
conc. conc. e.g. failure of contraception with oral e.g. failure of contraception with oral
contraceptives when given with Rifampin contraceptives when given with Rifampin
(Inducer) . (Inducer) .
2. 2. Increased toxicity of drugs, activated to toxic Increased toxicity of drugs, activated to toxic
metabolites. metabolites. e.g. Acute paracetamol toxicity e.g. Acute paracetamol toxicity
occurs at lower doses in patients receiving occurs at lower doses in patients receiving
enzyme inducers. enzyme inducers.
3. 3. Pharmacokinetic tolerance Pharmacokinetic tolerance- -if the drug induces if the drug induces
its own metabolism (auto its own metabolism (auto- -induction) induction)
e.g. Carbamazepine, Rifampin. e.g. Carbamazepine, Rifampin.
51
4. 4. Faster metabolism of Faster metabolism of some endogenous some endogenous
substrates (steroids, bilirubin) substrates (steroids, bilirubin)
5. 5. Precipitation of acute intermittent porphyria: Precipitation of acute intermittent porphyria:
Increased porphyrin synthesis by derepressing Increased porphyrin synthesis by derepressing
- -aminolevulenic acid synthetase. aminolevulenic acid synthetase.
6. 6. Intermittent use of an inducer Intermittent use of an inducer may interfere with may interfere with
dose adjustment of drugs prescribed on regular dose adjustment of drugs prescribed on regular
basis basis
e.g. oral anti e.g. oral anti- -coagulants, oral hypoglycaemics, coagulants, oral hypoglycaemics,
anti anti- - epileptics, anti epileptics, anti- -hypertensives hypertensives
Consequences oI Microsomal Enzyme Induction Consequences oI Microsomal Enzyme Induction
52
Drugs whose metabolism is significantly affected Drugs whose metabolism is significantly affected
by enzyme induction are by enzyme induction are
Phenytoin, WarIarin, Phenytoin, WarIarin,
Tolbutamide, Chloramphenicol, Tolbutamide, Chloramphenicol,
Oral contraceptives, Imipramine, Oral contraceptives, Imipramine,
Doxycycline, Theophylline, Doxycycline, Theophylline,
GriseoIulvin, Phenylbutazone GriseoIulvin, Phenylbutazone
Consequences oI Microsomal Enzyme Induction Consequences oI Microsomal Enzyme Induction
53
Possible uses oI enzyme induction Possible uses oI enzyme induction
1. Congenital non 1. Congenital non- -haemolytic jaundice: haemolytic jaundice:
phenobarbitone causes rapid clearance oI jaundice. phenobarbitone causes rapid clearance oI jaundice.
2. Cushing`s syndrome: 2. Cushing`s syndrome: phenytoin may reduce the phenytoin may reduce the
maniIestations. maniIestations.
3. Chronic poisonings. 3. Chronic poisonings.
4. Liver disease. 4. Liver disease.
54
En;yme Inhibifion En;yme Inhibifion
efinition: efinition: %his is o phenomenon in which %his is o phenomenon in which
cerfoin drugs moy cerfoin drugs moy inhibit uctivity of inhibit uctivity of
CYP40 enzymes CYP40 enzymes & & effecfiveIy reduce fhe effecfiveIy reduce fhe
mefoboIism of pofenfioI subsfrofes, mefoboIism of pofenfioI subsfrofes,
increosing pIosmo IeveIs & Ieoding fo foxicify. increosing pIosmo IeveIs & Ieoding fo foxicify.
55
En;yme Inhibifors En;yme Inhibifors
#eversibIe inhibitor #eversibIe inhibitor- - rug or ifs mefoboIife rug or ifs mefoboIife
form reversibIe compIex wifh iron of CYP form reversibIe compIex wifh iron of CYP
heom heom compefifive inhibifion compefifive inhibifion
IrreversibIe /Suicide inhibitors IrreversibIe /Suicide inhibitors rugs rugs
form reocfive mefoboIife which modify form reocfive mefoboIife which modify
CYP4b0 Apoprofein or frogmenf heom CYP4b0 Apoprofein or frogmenf heom
moiefy. moiefy.
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#eversibIe Enzyme Inhibitors #eversibIe Enzyme Inhibitors
Cimefidine , Iefocono;oIe , Isonio;id , Cimefidine , Iefocono;oIe , Isonio;id ,
Mefronido;oIe ,veropeminoI Mefronido;oIe ,veropeminoI
Eryfhromycin , %roIeondomycin , Eryfhromycin , %roIeondomycin ,
Furonocoumorines Furonocoumorines in in 0rope fruif juice 0rope fruif juice
IrreversibIe / SuiciduI Inhibitors IrreversibIe / SuiciduI Inhibitors
ChIoromphenicoI ChIoromphenicoI PropyIfhiourociI PropyIfhiourociI
Secoborbifone Secoborbifone SpironoIocfone SpironoIocfone
En;yme Inhibifors En;yme Inhibifors
57
CIinicuI significunce CIinicuI significunce
En;yme Inhibifors En;yme Inhibifors
58
Age & Sex Age & Sex
Etreme of uge Etreme of uge---- ---- sIower metuboIism sIower metuboIism
Fetus und neonute Fetus und neonute ure vuInerubIe to toic ure vuInerubIe to toic
effects of drugs becuuse; effects of drugs becuuse;
Weuk biotrunsformution Weuk biotrunsformution
PoorIy deveIoped PoorIy deveIoped
Immuture mechunisms for ecretion, Immuture mechunisms for ecretion,
CYP 40 deveIop neur uduIt uctivity within u CYP 40 deveIop neur uduIt uctivity within u
few months other Phuse 11 enzyme deveIop few months other Phuse 11 enzyme deveIop
more sIowIy more sIowIy
59
In neonutes In neonutes, porficuIorIy premofure bobies , porficuIorIy premofure bobies
Peduced gIucuronoid conjugofion Peduced gIucuronoid conjugofion
yperbiIirubinemio, risk of kernicfrus. yperbiIirubinemio, risk of kernicfrus.
Increosed foxicify of chIoromphenicoI ond opioids Increosed foxicify of chIoromphenicoI ond opioids
In EIderIy In EIderIy en;yme sysfems decreose en;yme sysfems decreose
renoI funcfion decIines renoI funcfion decIines
Age & Sex Age & Sex
60
ief & EnvironmenfoI Focfors ief & EnvironmenfoI Focfors
ChorcooI broiIed food, cruciferous ChorcooI broiIed food, cruciferous
vegefobIes, Smoking, AIcohoIism, Exposure fo vegefobIes, Smoking, AIcohoIism, Exposure fo
pesficides pesficides- - En;yme inducers. En;yme inducers.
0rope fruif juice confoins Furonocoumorines. 0rope fruif juice confoins Furonocoumorines.
En;yme inhibifor En;yme inhibifor
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Inferocfions befween rugs & Inferocfions befween rugs &
Endogenous compounds Endogenous compounds
rugs muy compete for these substrutes, rugs muy compete for these substrutes,
---- ---- gIututhione gIucuronic ucid & suIfute, gIututhione gIucuronic ucid & suIfute,
62
PuthoIogicuI stutes of Iiver CVS PuthoIogicuI stutes of Iiver CVS
Iungs endocrines, Iungs endocrines,
63
NutritionuI stutus: sturvution NutritionuI stutus: sturvution
muInutrition muInutrition
64
GLNL1I A1ORS. GLNL1I A1ORS.
Atypical pseudocholinesterase: Atypical pseudocholinesterase:- - Succinylcholine Succinylcholine
(Suxamethonium) is hydrolysed by pseudocholinesterase. (Suxamethonium) is hydrolysed by pseudocholinesterase.
Genetically abnormal pseudocholinesterase Apnoea. Genetically abnormal pseudocholinesterase Apnoea.
Acetylation status: Acetylation status: Slow & Iast acetylators Inherited as an Slow & Iast acetylators Inherited as an
autosomal recessive trait Slow acetylator phenotype autosomal recessive trait Slow acetylator phenotype about S0 about S0
0f blacks & white in the USA Much less common in Asians & 0f blacks & white in the USA Much less common in Asians &
eskimos eskimos
Genetically determined defects in the CYP dependent oxidative Genetically determined defects in the CYP dependent oxidative
metabolism of: metabolism of:
Debrisoquin, Phenacetin, Phenformin (extensive metabolizers Debrisoquin, Phenacetin, Phenformin (extensive metabolizers
and poor metabolizers) and poor metabolizers)
Hydroxylation of anticonvulsant Mephenytoin: Hydroxylation of anticonvulsant Mephenytoin: Poor Poor
hydroxylators & Iast hydroxylators hydroxylators & Iast hydroxylators