Pharmacokinetics:: Metabolism

Pharmacokinetics: Metabolism
Dr. Irfan Ahmad Khan

Assistant Professor
Deputy Co-ordinator, ADRMC, JNMC
No. Competencies
PH1.4 Describe absorption, distribution, metabolism &
excretion of drugs
At the end of the discussion you
should be able to understand:
• What is Biotransformation of Drug?
• Where does Biotransformation takes place?
• What is first pass metabolism?
• What are Prodrugs?
• What are Phase I & Phase II Reactions?
• What is the importance of Microsomal Enzymes?
Pharmacokinetics: Metabolism
Conversion of Non- Polar compounds into

polar water soluble products inside body
• NO Biotransformation
 Benzyl penicillin (excreted unchanged)
• Partial Biotransformation
 Aspirin, Paracetamol (Excreted unchanged
and as metabolite)
• Complete Biotransformation
 Chloramphenicol (Excreted as metabolite)
Why biotransform
To excrete the toxic chemicals -

Xenobiotics
Where Biotransformation takes place?
• Liver
• Other tissues: Intestine, Lungs, Plasma,
Mucosa
• Colon Bacteria: Azo Reduction, hydrolytic
reactions
Wavelength
• CYP P : Smooth Endoplasmic

450 Reticulum
Pink
First Pass metabolism/ First Pass Effect
• Metabolism of the drug before it reaches
the systemic circulation
• Lignocaine, morphine, GTN

Prodrug
• A precursor of a drug
• It is a medication or compound that, after

administration, is metabolized into a
pharmacologically active drug
• Eg. Bacampicillin is a prodrug of ampicillin

Levodopa Dopamine
• To improve the pharmacokinetics of the drug

Active Drug
Metabolized Digitoxin Digoxin

into active
metabolite
ProDrug Active Drug

Levodopa
Dopamine
Metabolism Lignocaine
Ibuprofen
Inactivation of the drug

Phases of Metabolism of Drugs
Unchanged
Active Drug
Excretion
Phase I Reaction
Phase II Reaction
Metabolites
Metabolites
Excretion Excretion
Excretion
Phase Vs Phase II
I
Phase I Phase II Reactions
Reactions
Cytochrome P450 Conjugation Enzyme
(Microsomal System) (Non Microsomal)
Inducible Usually Non-Inducible
Usually Transferase
Usually Oxidative
Enzymes
Enzymes
Addition of OH- or H+ Conjugation of a Moiety
(usually Hydrocarbon)
Degenerative Rxn Additive Rxn
Products are Usually Products are always

water soluble water soluble
Biotransformation
COOH Phase I COOH Phase II COOH
O Hydrolysis OH
UDP- GT
Glucuronosyl Conjugation O O OH
Salicylic Acid
O CH3
Aspirin COOH OH
OH
Oxidation
Reduction UGT (UDP- Glucuronosyl Transferase)  Aspirin
Cyclization GST (Glutathione -S- Transferase)  Paracetamol

Decyclization
NAT (N- Acetyl Transferase)  Isoniazid
Hydrolysis
SULT (Sulfotransferase)  Sex Hormones/ Steroids
Mnemonic: COW  cycle, oxidation,

Phase I - Oxidation
 Most important drug metabolizing reaction – addition of
oxygen or (–ve) charged radical or removal of hydrogen
or (+ve) charged radical
 Various oxidation reactions are – oxygenation or

hydroxylation of C-, N- or S-atoms; N or O- dealkylation
 Examples – Barbiturates, phenothiazines, paracetamol

and steroids
Phase I - Oxidation
• Involve – CYP P-450 monooxygenases, NADPH and Oxygen
• >100 CYP P-450 isoenzymes and grouped into more than

20 families – 1, 2 and 3 …
• Sub-families – A, B, C ….
• In human - only 3 isoenzyme families important – CYP1,

CYP2 and CYP3
• CYP 3A4/5 carry out biotransformation (30–50% drugs)
• In addition to liver, this isoforms are expressed in intestine

(responsible for first pass metabolism) and kidney
• Inhibition of CYP3A4 by erythromycin, clarithromycin,
ketoconzole, itraconazole, verapamil, diltiazem and a
constituent of grape fruit juice is responsible for unwanted
interaction with terfenadine and astemizole
• Rifampicin, phenytoin, carbmazepine, phenobarbital are

inducers of CYP3A4
Oxidation - CYP
CYP3A4/5
Nonmicrosomal Enzyme Oxidation
 Some Drugs are oxidized by nonmicrosomal

enzymes (mitochondrial and cytoplasmic) –
Alcohol, Adrenaline, Mercaptopurine
 Alcohol – Dehydrogenase
 Adrenaline – MAO and COMT
 Mercaptopurine – Xanthine oxidase

Phase I - Reduction
 This reaction is conversed of oxidation and involves
CYP 450 enzymes working in opposite direction
 Examples - Chloramphenicol, levodopa, halothane and

warfarin
DOPA-decarboxylase
Levodopa (DOPA) Dopamine
Phase I - Hydrolysis
 Cleavage of drug by taking up of a molecule of water
 Similarly amides and polypeptides are hydrolyzed by
amidase and peptidases
 Occurs in liver, intestines, plasma and other tissues
 eg - Choline esters, procaine, lidocaine, pethidine,
oxytocin
Esterase
Ester + H20 Acid + Alcohol
Phase I – contd.
 Cyclization: is formation of ring structure from a straight

chain compound, e.g. Proguanil
 Decyclization: is opening up of ring structure of the cyclic

molecule, e.g. phenytoin, barbiturates
Phase II metabolism
 Conjugation of drug or its phase I metabolite with an

endogenous substrate  polar highly ionized organic
acid to be excreted in urine or bile - high energy
requirements
Phase II metabolism
Glucoronide conjugation –
most important synthetic reaction
Compounds with hydroxyl or carboxylic acid group are
easily conjugated
eg: Chloramphenicol, aspirin, morphine, metronidazole,
bilirubin, thyroxine
Drug glucuronides, excreted in bile, can be hydrolyzed in
gut by bacteria, producing beta-glucoronidase - liberated
drug is reabsorbed and undergoes same fate - enterohepatic
recirculation (e.g. chloramphenicol, phenolphthalein, OCP)
and prolongs their action
Phase II metabolism – contd.
 Acetylation: Compounds having amino or hydrazine
residues are conjugated with the help of acetyl CoA,
e.g. sulfonamides, isoniazid
Genetic polymorphism (slow and fast acetylators)
 Sulfate conjugation: Phenolic compounds and steroids

are sulfated by sulfokinases, e.g. chloramphenicol,
adrenal and sex steroids
Phase II metabolism – contd.
 Methylation: Amines and phenols can be methylated.
Methionine and cysteine act as methyl donors.
 Examples: adrenaline, histamine, nicotinic acid
 Ribonucleoside/nucleotide synthesis:activation of
many purine and pyrimidine antimetabolites used in
cancer chemotherapy
Factors affecting Biotransformation
 Factors affecting biotransformation
 Concurrent use of drugs: Induction and inhibition
 Genetic polymorphism
 Pollutant exposure from environment or industry
 Pathological status
 Age
Enzyme Inhibition
 One drug can inhibit metabolism of other – if utilizes
same enzyme
 However not common because different drugs are
substrate of different CYPs
 A drug may inhibit one isoenzyme while being substrate
of other isoenzyme – quinidine (CYP3A4 & 2D6)
 Rapid
 Some enzyme inhibitors – Omeprazole, metronidazole,
isoniazid, ciprofloxacin and sulfonamides
Microsomal Enzyme Induction
• CYP3A - antiepileptic agents - Phenobarbitone, Rifampicin
and glucocorticoid
• CYP2E1 - isoniazid, acetone, chronic use of alcohol
• Other inducers – cigarette smoking, charcoal broiled meat,
industrial pollutants – CYP1A
• Consequences of Induction:
• Decreased intensity – Failure of OCPs
• Increased intensity – Paracetamol poisoning (NAPQI)
• Tolerance – Carbmazepine
• Endogenous substrates are metabolized faster –
steroids, bilirubin
Possible uses of enzyme induction
1. Congenital nonhaemolytic jaundice: It is due to
deficient glucuronidation of bilirubin; phenobarbitone
hastens clearance of jaundice.
2. Cushing’s syndrome: phenytoin may reduce the

manifestations by enhancing degradation of adrenal
steroids which are produced in excess.
3. Chronic poisonings: by faster metabolism of the

accumulated poisonous substance.
4. Liver disease.
Hofmann elimination
• Inactivation of drug in body fluids by
spontaneous molecular rearrangement without
the agency of any enzyme, e.g. atracurium
Questions!!

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Pharmacokinetics: Metabolism

Dr. Irfan Ahmad Khan

Conversion of Non- Polar compounds into

To excrete the toxic chemicals -

• CYP P : Smooth Endoplasmic

• Lignocaine, morphine, GTN

• It is a medication or compound that, after

• Eg. Bacampicillin is a prodrug of ampicillin

• To improve the pharmacokinetics of the drug

Metabolized Digitoxin Digoxin

ProDrug Active Drug

Inactivation of the drug

Inducible Usually Non-Inducible

Degenerative Rxn Additive Rxn

Products are Usually Products are always

Cyclization GST (Glutathione -S- Transferase)  Paracetamol

Mnemonic: COW  cycle, oxidation,

 Various oxidation reactions are – oxygenation or

 Examples – Barbiturates, phenothiazines, paracetamol

• >100 CYP P-450 isoenzymes and grouped into more than

• In human - only 3 isoenzyme families important – CYP1,

• CYP 3A4/5 carry out biotransformation (30–50% drugs)

• In addition to liver, this isoforms are expressed in intestine

• Rifampicin, phenytoin, carbmazepine, phenobarbital are

 Some Drugs are oxidized by non- microsomal

 Mercaptopurine – Xanthine oxidase

 Examples - Chloramphenicol, levodopa, halothane and

 Cyclization: is formation of ring structure from a straight

 Decyclization: is opening up of ring structure of the cyclic

 Conjugation of drug or its phase I metabolite with an

Genetic polymorphism (slow and fast acetylators)

 Sulfate conjugation: Phenolic compounds and steroids

2. Cushing’s syndrome: phenytoin may reduce the

3. Chronic poisonings: by faster metabolism of the

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