Drug metabolismsvpp

Def :-Conversion of a drug from one chemical form to
another.
 Penicillin--------pencilloic acid
Biotransformation of Xenobiotics...
1
Biotransformation
 Purpose
 Converts lipophilic to hydrophilic compounds
 Facilitates excretion

 Pharmacological inactivation
ex: Phenytion to p-hydroxy phenytion
Salicylic acid to Salicyluric acid
 No change in pharmacology activity
ex: codeine to Morphine
Imipramine to Desipramine
 Toxicological activation
ex: Paracetamol to Imidoquinone of N-hydroxylated metabol
 Phrmacologic activation(prodrug)
ex:Enalapril to Enalaprilat
 Change in pharmacological activity:
ex: Iproniazid(anti depressent) to isoniazid(antitubercular)
2

Hepatic metabolism
 “Liver”--- Primary site of metabolism
 Contains high amounts of various enzymes
Extrahepatic metabolism
 Order is as – Liver > Lungs > Kidneys > Intestine >
Placenta > Adrenals > Skin.
 Brain, testes, muscles, spleen etc., metabolize drugs
to small extent.
3

 Two types of enzyme systems involved
 Microsomal
 Non-Microsomal
Microsomal –
 Associated with the ER of liver,
 membrane bound enzymes,
 selective towards lipid soluble substrates, and
converts them into water soluble substrates.
 Cytochrome enzymes are microsomal enzymes.
4

Non Microsomal –
 Associated with mitochondria but not ER, water
soluble enzymes and
 act on water soluble substrates.
 Peroxidases, dehydrogenases, and esterases
are non-microsomal enzymes.
5

6
Phase I Phase II
OH O-SO3
Phases

 These are also called as functionalization
reactions.
 Either introduces or unmasks the already
present functional group in the molecule.
 Also called as Asynthetic reactions because no
new compound is synthesized by this
functionalization.
7

 These are also called as synthetic reactions
because of synthesis of a new compound by
the addition of small polar endogenous
molecules like glucuronic acid, sulfate, glycine
etc to either unchanged drug or to the phase I
product.
 Conjugation reactions
 Called as the real detoxification process.
8

Enzyme Phase I Phase I I
Types of reactions Hydrolysis
Oxidation
Reduction
Conjugations
Increase in
hydrophilicity
Small Large
General mechanism Exposes functional
group/ Polar
compound added to
functional group
Polar compound added
to functional group
Consquences May result in
metabolic activation
Facilitates excretion
Types of Enzymes
invoved
Microsomal and also
Non-microsomal
Only microsomal
9

10
Phase 2 reactions / Conjugations
• -OH, -SH, -COOH, -CONH with glucuronic acid
to give glucuronides
• -OH with sulphate to give sulphates
• -NH2, -CONH2, aminoacids, sulpha drugs with
acetyl- to give acetylated derivatives
• -halo, -nitrate, epoxide, sulphate with glutathione
to give glutathione conjugates
all tend to be less lipid soluble and therefore better excreted.
Phase 1 reactions
• -OH, -SH, -COOH, -CONH

 Oxidation is a process which invovles in the
addition of oxygen or removal of hydrogen
 It increases the hydrophilicity of drugs by
introducing polar group -OH
 Enzymes are located in microsomes
 Mixed function oxidases
 R-H+O2+NADPH+H+
R-OH+H2O+NADP+
 Mono-oxygenases
11

 Addition of hydrogen or removal of oxygen
 Mixed function oxidase works reverse
 Reduction of carbonyls(aldehyde and ketones)
 Example
14
.

 Hydrolysis of Esters
15
.

 Hydrolysis of Amides
R-CO-NH-Rl
RCOOH + Rl
NH2
16
H2O
H2O
.

 Conjugation with Glucuronic acid
 Conjugation with Sulphate moieties
 Conjugation with Glutathione
 Acetylation reaction
 Methylation reaction
17

 Also known as Gluco-uronidation
 Most important and Common reaction
 The free carbonyl function of glucuronic acid ionized at
plasma and urine pH – increases water solubility and
elimination
 The enzyme system of glucuronidation is associated with
the microsomal enzyme system of Phase I reactions
 D-glucuronic acid is a derivtive of D-Glucose
 Since UDPGA is involved in the Glycogen synthesis and
Glucuronidation, this type of conjugation is the commonest
form because of UDPGA available throughout the body
 Degree of Conjugation is very high (Quantitatively) and
mammals produce the highest amount of glucuronides
18

19
Liver has several soluble UDP-Gluc-transferases
.

 Mainly catalyzed by non-microsomal enzymes
Functional Groups Compounds
undergoing sulfate
conjugation
Phenols Paracetamol and
Salbutamol
Alcohols Aliphatic C1
to C5
Aryl amines Aniline
20

21
Examples: ethanol, p-hydroxyacetanilide, 3-hydroxycoumarin
(PAPS, 3’-phosphoadenosine-
5’-phosphosulfate)
ROH
ROSOH
O
O
H H
NH2
N
NN
N
OH
O
H H
HO
O P
OH
O
O S
OH
O
O
+
.

 It is a tripeptide with strong nucleophilic character due
to the –SH group in its structure and so highly reactive
with electrophilic metabolite.
 Nucleophilic groups like –OH, -NH2 and –SH present
in the tissue reacts with the electrophilic metaboites
leading to the accumulation and causes toxicities like
Carcinogenesis, tissue necrosis, teratogenesis and
mutagenesis that are avoided by the glutathione
conjugation
 Examples – Alkyl nitrates, Sulfonates,
Organophosphates, epoxides and lactones etc.
22
.

23
Conjugation with Glutathione
.
N-acetyl-p-
benzoquinonimine

 Important pathway for the drug containing
primary amine groups
 Ex. Histamine, GABA, Dapsone,
Sulphanilamide, Sulphapyridine, INH
24
.

 Metabolites are formed are not polar/water
soluble
 Metabolites produced same or greater
pharmacological activity than the parent drug
 Ex. Morphine formed from Nor-Morphine
25

 Race - fast and slow isoniazid acetylators,
50% Brits, 13% Egyptians.
 age (reduced in aged patients & children)
 sex (women slower ethanol metabilizers)
 species (phenylbutazone 3h rabbit, 6h horse, 8h
monkey, 18h mouse, 36h man)
 clinical or physiological condition(Liver diseases)
 other drug administration (induction (not CYP2D6 ) or
inhibition)
26

Inducers Drugs with enhanced
metabolism
Barbiturates Phenytoin, Coumarin,
Testosterone
Alcohol Pentobarbital, Coumarin,
Phenytoin
Phenytoin Coumarin, Oral Contraceptives,
Tolbutamide
Rifampicin Oral Contraceptives,
Tolbutamide, Coumarin
27

Inhibitors Drugs with
decreased
metabolism
MAO Inhibitors Barbiturate, Tyramine
Coumarins Phenytoin
Allopurinol 6-mercaptopurine
PAS Phenytoin,
Hexobarbital
28

1.Biotransformation: Converts hydrophilic to lipophilic
compounds
2. Phases II: Fuctionalization reaction
3. “Liver”--- Primary site of metabolism
4. Conjugation reactions
5.
Phase I Phase II
OHO-SO3

30
6. Phase I: small polar endogenous molecules like glucuronic
acid, sulfate, glycine
7. MAO Inhibitors- Tyramine (↓ or Metabolism)
8. Barbiturates, Rifampicin- Coumarins (↓ or Metabolism)

Drug metabolismsvpp

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