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Drug Metabolism
Dr.Abdul latif Mahesar
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
Drug metabolism (biotransformation)
It is the type of chemical reactions which
leads to modification of drugs
Drugs are converted from one form to an other to make
them more active ,less active and finally inactive and to
leave the body
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 Sites of metabolism
Hepatic: microsomes , mitochondria, cytoplasm
Extrahepatic: lung ,blood ,skin , GIT, kidney.
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Microsomes:
 Microsomal enzyme system→ mixed function oxidase →
mono-oxygenases
 Its components include
Cytochrome P450
Flavinoprotein (co-enzymes in redox reaction) NADPH
Molecular oxygen,
Drug + enzyme +oxygen molecule +NADPH +Flavoprotein
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
Mitochondria:
mono-amine oxidase enzyme (MAO)
Acetylation

Cytoplasm:
Alcohol dehydrogenase

Blood (plasma)
Estrases
Amidases
Catechol-o methyltransferases(COMT)

Intestinal Mucosa and Lumen:
GIT flora:Glucouronidase ,Asoreductases.

GIT mucosa : Monoamime oxidase (MAO) ,
Sulphatase
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Types
of
Reactions
Metabolic
Phase I reactions
Phase II reactions
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Phase-I Reactions
 Metabolism brings about a change in the molecule
by oxidation ,reduction ,or hydrolysis and often
introduces a chemically active site into it. The new
metabolite may retain biological activity but have
different pharmacokinetic properties e.g. short or
long half life, they may become inactive or more
toxic.
Oxidation:
 The most important and main single group of
reactions is the oxidations.
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Characteristics of Phase I
Products (Result of Drug Metabolism)
 1. Inactivation (abolish the activity
Oxidation of Phenobarbital and alcohol
Hydrolysis of acetylcholine
 2. conversion of active drug to another active
one.
Diazepam →oxydiazepam
Codeine ,heroin → Morphine
Phenylbutazone → oxyphenylbutazone
Propranolol → 4-hydroxypropranolol
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 3. conversion of drug to toxic metabolites:
Paracetamol → acetaminopen (hepatic toxicity)
Halothane → metabolite hepatotoxicity
 4. Activation of pro-drug
Chloral hydrate → trichloroethanol
Enalapril
Enalaprilat
 5. Product might undergo phase II
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Phase-I Reactions :
 Make the drug more polar → more water soluble.
(oxidation ,reduction, hydrolysis)
 Oxidation reaction:
introduces functional group (OH,NH2,SH)
Can be mirosomal or nonmicrosomal
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Microsomal:
 Drug + O2 + NADPH + H→ changed drug + H2O + NADP
e.g. 1. Aliphatic hydroxylation
Phenobarbital → hydroxyphenobarbital
2. Aromatic hydroxylation
Phenacetin→ 2-hydroxyphenacitin (paracetamol)
3. Oxidation of amine
Aniline → nitrobenzene
4. sulphoxidation
Parathione → paroxon
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
Reduction Reactions:
Microsomal or non-microsomal
Microsomal:
nitrobenzene → aniline
NO2 →NH2
Non-Microsomal:
Chloral hydrate → trichloroethanol

Hydrolysis:
Non-microsomal ONLY
Ester-C-O and amides-C-N
Acetylcholine → choline +acetate(ester)
Procainamide (lidocaine) (amide)
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Non-microsomal:
 Oxidation by soluble enzyme in cytosol or mitochondria
of cells
e.g
1. dehydrogenases and oxidases
Ethanol → acetaldehyde → acetic acid.
Methanol → formaldehyde → formic acid
CH3CH2OH→ CH3CHO→CH3COOH
2. monoamide oxidase(noradrenaline)
3. Hypoxanthine → xanthine → uric acid
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Phase-II Metabolism
 It involves union of the drug with one of several
polar(water soluble )endogenous molecules that are
product of intermediatory metabolism to form water
soluble conjugate which is readily eliminated by the
kidney or if the molecular weight is more than 300 in
the bile
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Phase II Conjugation Reaction
e.g.
Morphine,paracetamol and salicylates form conjugates with glucuronic acid
derived from glucose
 Oral contraceptive steroids form sulphates
 Phenalzine and dapsone are acetylated
 conjugation with more polar molecule is also a mechanism by which
natural substances are eliminated eg.bilirubin as glucuronide and estrogen
as sulphate.
 Phase –II reactions almost invariably terminates biological activity
 ALL is non-microsomal enzyme Except glucouronidation (catalyzed by
glucouronyl transferase )
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Characteristics of Phase II
Products
 Pharmacologically inactive
 More water soluble
→ to be excreted
 More readily excreted in urine
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Modulation of Liver Microsomal Enzymes
 Induction
 Inhibition
 Liver Microsomal Inducers
Alcohol
Barbiturates
Cigarette smoking
Phenytoin
Rifampicin
Spironalactone
Griseofulvin
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Enzyme Induction results in
 Increase metabolism of the inducer
 Tolerance: decreased pharmacological action of the drug
 Increase the metabolism of co-administered drug (drug
interaction)
Barbiturate +Warfarin
Phenytoin + Oral contraceptives
Rifampicin + Hydrocortisone
 Increased metabolite- mediated tissue toxicity
Paracetamol and phenacetin
 As therapy ( phenobarbitone + hyperbilirubinemia)
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Liver Microsomal Inhibitors
Cimetidine
Erythromycin
ketoconazole
Metronidazole
Probenecid
 Enzyme inhibition may
Retard the metabolism and excretion of the inhibitor and coadministered drugs
Prolong the action of the inhibitor and co-administered
drugs→ increased pharmacological activity.
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First Pass Metabolism
 A drug can be metabolized before the drug reaches the systemic
circulation so the amount reaching systemic circulation is less than
the amount absorbed
 Where ? Liver ,gut wall, lung
 Result:
low bioavailability
Short duration of action
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Factors affecting drug metabolism
Age: the enzyme system at birth especially in preterm
baby are functionally imature and especially for
oxidation and for conjugation with glucuronic acid.
 The drugs like chloramphenicol is unable to get
conjugated can cause fatal grey baby syndrome in
neonates .
 After first weeks of life the drug metabolic capacity
increases rapidly
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In elderly metabolism is reduced because liver mass
and liver blood flow are decreased .Metabolic
inactivation of drugs is slowed
Drugs persist for longer time and in higher
concentration the must be lowered e.g. tricyclic
antidepressants , antidysrhythmic drugs.
Enzyme induction process is also lessened
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 Pregnancy: Hepatic metabolism is increased
 This leads to increased clearance of drugs such as
phenytoin and theophylline
 Disease: Acute inflammatory disease of liver (viral
,alcoholic) and cirrhosis affect function of hepatocytes and
blood flow through the liver,this results in increased
systemic availability of drugs such as propranolol ,labatolol
especially which has normally high 1st pass metabolism,
and exhibit prolong half life and reduced clearance.
 Drug metabolism is accelerated in hyperthyroidism
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 Food: some specific dietary factors induce drug
metabolizing enzymes
e.g. alcohol, charcoal grilled beef, cabbage.
Protein malnutrition reduces hepatic metabolizing
capacity.
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