BIOTRANSFORMATION
DEFINITION
• Chemical alteration of a drug/chemical inside our
body is called as biotransformation/metabolism
Why Biotransformation?
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Most drugs are excreted by the kidneys
• For renal excretion drugs should:
– have small molecular mass
– be polar in nature
– not be fully ionized at body pH
Most drugs are complex and do not have these
properties and thus have to be broken down to
simpler products.
Why Biotransformation?
Drugs are lipophilic in nature
• Thus readily pass across biological barriers
• Strongly bound to plasma proteins
• This property also stops them from getting eliminated
They have to be converted to simpler hydrophilic
compounds so that they are eliminated and their action is
terminated.
Where Do Drug Biotransformations Occur?
• The liver is the principal organ of drug metabolism.
Other tissues that display considerable activity include the
• gastrointestinal tract,
• lungs,
• skin,
• kidneys.
Who is carrying out Drug
Biotransformations?
• Although drug biotransformation in vivo can occur by
spontaneous, non-catalyzed chemical reactions, the
vast majority of transformations are catalyzed by
specific cellular enzymes.
• At the sub cellular level, these enzymes may be located
in the endoplasmic reticulum, mitochondria,cytosol,
lysosomes, or even the nuclear envelope or plasma
membrane.
Drug metabolizing enzymes
• Cytochrome P450 (CYP 450) is the major drug metabolizing
enzyme system in the body.
• Also known as “mixed function monooxygenases”
• Liver and gut wall have the greatest concentration of P450
• Almost all tissues in the body have some P450
(Lungs, Kidney, Skin, Brain, etc)
CYP Isoforms
• CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4 appear to be the major
forms that carry out metabolic reactions .
CYP 450 Isoform
DRUG SUBSTRATE
1A2
Theophylline , warfarin
2A6
Coumarine
2C9
Ibuprofen , phenytoin
2D6
Haloperidol, tricyclic antidepressants
2E1
Halothane , ethanol
3A4
Acetaminophen,
progesteroneterfenadine,
testosterone,
CYP Isoforms
% DRUGS METABOLIZED BY CYP ENZYMES
CYP 2C19
11%
CYP 2C9
14%
CYP2D6
23%
CYP 1A2
14%
CYP 3A4-5
33%
CYP2E1
5%
Biotransformation : Consequences
1. Active drug  Inactivation
morphine  6-hydroxy morphine
2. Active drug  Active metabolite
digitoxin digoxin
3. Inactive drug(prodrug)  Active drug
L-dopa dopamine
Enalapril Enalaprilat
Bacampicillin  ampicillin
Phases
• Biotransformation reactions can be:
– Phase I reactions
– Phase II reactions
Phase I reactions
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Catabolic in nature
– e.g. Oxidation, Reduction, Hydrolysis
End-products are chemically more reactive
Metabolites are usually more polar than the parent
drug.
• Introduce a reactive group – ie functional group
• The functional group becomes the starting point for
Phase II reaction.
Phase I reactions
• Cytochrome P450 is the major enzyme system
(Oxidations, reductions, etc.)
Phase I metabolites may be:
• Inactive
• Equally Active
• More Active
• Toxic
• Activated - “prodrug”
• Polar metabolites may be excreted.
Phase I reactions
Reaction
example
1. Oxidation
Warfarin , morphine
2. Reduction
Halothane, chloramphenicol
3. Hydroysis
Lignocaine, procaine
4. Cyclization
Proguanil
5. Decyclization
Phenytoin, barbiturates
Phase II reactions
• Synthetic processes
• If a drug is not rendered to hydrophilic
molecule by Phase-I reactions, Phase –II is
required.
• An endogenous substrate is coupled to an
existing (or phase I formed) conjugation site.
• Forms a highly polar conjugate
• Phase II reactions usually occur after Phase I
but can also take place earlier than Phase I
Phase II reactions
Type of Conjugation
Examples
Glucuronidation
Morphine, acetaminophen,
diazepam
Acetylation
Sulfonamides,isoniazid
Glutathione conjugation
Ethacrynic acid
Glycine conjugation
Salicylic acid, benzoic acid,
nicotinic acid
Sulfate conjugation
acetaminophen, methyldopa
Methylation
Dopamine, epinephrine
Water conjugation
Carbamazepine, Leukotriene A4
Drug molecule
I
More hydrophilic
metabolite
II
Conjugate
Bile
Kidney
Intestines
Urine
Feces
De-conjugation
and reuptake
(entero-hepatic
cycling)
Enzyme Induction
• Reversible increase in enzyme concentration
• Resulting from administration of certain drugs
• May increase the metabolism of other drugs
taken concurrently
Consequences:
• Decreased duration of action of an active drug
due to fast inactivation .
• Increased intensity of action of an inactive drug
due to fast activation
Enzyme Induction
Inducer
Drug whose metabolism is enhanced
Griseofulvin
Warfarin
Barbiturates
Phenytoin, testosterone, estradiol, digoxin
Phenytoin
OCPs, Theophylline
Rifampin
OCPs, coumarin anticoagulants,
propranolol
Enzyme Inhibition
• Some drugs can block P450 enzymes that metabolise
other drugs
• Unlike induction, enzyme inhibition usually begins
with the first dose of the inhibitor.
Consequences:
• May increase serum concentrations of second drug
• Can lead to toxicity
Enzyme Inhibition
Inhibitor
Drug whose metabolism is Inhibited
Cimetidine
Warfarin
Disulfiram
Ethanol
Ketoconazole
Terfenadine
Grape Fruit Juice
Alprazolam, cisapride