Bachelor of Pharmacy
Fourth Semester
BP 404 T
Pharmacology-I
Dr Shvetank Bhatt
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Biotransformation (Metabolism) of Drugs
Onset depends upon
Absorption
Distribution
Duration of action depends upon
Tissue redistribution
Elimination
All chemicals except nutrients- Xenobiotics
A. General properties
1. Biotransformation is a major mechanism for drug
elimination;
Chemical conversion of one form to another from lipid soluble to
water soluble form
It is detoxification process
Active form to inactive metabolite
Results of biotransformation:
Production of metabolites that are more polar than the
parent drug
usually terminates the pharmacologic action of the
parent drug
After phase I reactions, similar or different
pharmacologic activity, or toxicologic activity.
Results of biotransformation
Biotransformation of Drugs
Metabolites and Relative Activity of Drugs
•Pharmacologic inactivation
Amphetamine to phenyl acetone
Phenobarbital to hydroxyphenobabital
•No change in Pharmacological Activity
Active to active
Amitriptyline to nortriptyline
Imipramine to desipramine
•Toxicological activation
Isoniazid to tissue acylating intermediate
•Pharmacological Activation
Inactive to active
Aspirin to salicylic acid
Phenacetin to paracetamol
Enalapril to enalaprilat
•Change in Pharmacological Activity
Iproniazid to isoniazid
Diazepam to oxazepam
In comparison with xenobiotics endogenous substance metabolized faster: soft drugs
Drug metabolizing organs
Liver is the heart of metabolism
Because of its relative richness of enzymes in large
amount.
Schematic chart of metabolizing organ (decreasing
order)
Metabolism other than liver is known as extrahepatic
Liver > lungs > Kidney > Intestine > Placenta > Skin
> Brain > Testes > Muscle > Spleen
Microsomal Enzymes
• Derived from rough
endoplasmic reticulum of
hepatic cells
• Other areas:
• Kidney
Non-microsomal
• Lungs
• Intestinal mucosa enzymes
• Found in the cytoplasm and
mitochondria of hepatic cells
Microsomal enzymes
The intact lipoidal membrane-bound- selective
towards lipid soluble substrate
Interacts with Lipid soluble substrates
Nonspecifically
Lipid Polar water
No. of oxidative, reductive and hydrolytic reactions
Non microsomal enzymes
Cytosol
Few oxidative reactions, a number of hydrolytic and reductive
Reaction and conjugation other than glucuronidation
Act on comparative water soluble xenobiotics
Metabolic reaction:
Phase I reaction Phase II reaction
Oxidation
Conjugation
Reduction
Hydrolysis
Phase I:
A polar functional group is either introduced or
unmasked if already present on the otherwise lipid
soluble Substrate,
E.g. –OH, -COOH, -NH2 and –SH.
Thus, phase I reactions are called as functionalization
reactions.
Phase I reactions are Non-synthetic in nature.
Phase I metabolite goes for phase II reactions
Oxidation
Ring hydroxylation : Phenobarbital tp p-hydroxyphenobarbital
N-oxidation : Imipramine to imipramine N-oxide
O-dealkylation : Codeine to morphine
Oxidative deamination: Amphetamine to phenylpropanone-2
Reductive reactions:
Reduction
Chloral hydrate to trichloro ethanol
Acetaphenone to methyl phenyl carbinol
Hydrolytic Reactions
Esters, ethers, amides, hydrazides
Aspirin to salicylic acid
Procainamide to PABA
Carbamazepine to iminostilbine
Phase II
Phase II - combines functional group of compound
with endogenous substance
E.g. Glucuronic acid, Sulfuric acid, Amino Acid, Acetyl.
Products usually very hydrophilic
The final compounds have a larger molecular weight.
Enzymes
Glucuronosyl Transferases
Sulfotransferases (ST)
Acetyltransferase
Methylases
Synthetic Reactions / Phase II
• These reactions usually involves covalent attachments
of small polar endogenous molecules such as
Glucoronic acid, Sulfate, Glycine to either unchanged
drugs or Phase I product having suitable functional
groups as COOH,-OH,-NH2,- SH.
• Thus is called as Conjugation reactions.
• Since the product formed is having high molecular
weight so called as synthetic reactions.
• The product formed is hydrophilic in nature with total
loss of pharmacologic activity so called as a true
detoxification reaction
Phase II
Glucuronide Conjugation
Methylation
Acetylation
Sulfate Conjugation
Conjugation With Alpha Amino Acids
Glutathione Conjugation
Glycine Conjugation
Glucuronide Conjugation: Also called as glucuronidation. D-Glucuronic acid is
derived from D-Glucose
COOH COOH COOH Benzoic acid
OH
OH
OH UDP OH
OH
OH
UDPGA Benzoic Acid Glucuronide Benzoic acid
Ex.
Chloramphenicol, Morphine, Salicylic Acid, Paracetamol
Factors affecting Biotransformation
1. Physicochemical properties of drug: Affects binding with particular enzymes
2. Chemical factors
a] Enzyme induction
I] Phenobarbital type inducers
eg. Barbiturate induces metabolism of coumarins, phenytoin
Alcohol induces the metabolism of pentobarbital, phenytoin
II] Polycyclic type inducers
eg. Cigarette smoke
Carbamazepine, meprobamate, cyclophosphamide, rifampicin - self induction
b] Enzyme inhibition:
eg. MAO inhibitor inhibits metabolism of barbiturates and tyramine
Coumarins inhibits metabolism phenytoin
3. Biological factors:
• Species difference: Metabolism of amphetamine and ephedrine
In men and rabbit by oxidative deamination
In rats by aromatic oxidation
• Strain difference: N-acetylation Black USA slow-48 fast -50
Japanese 87 13
• Sex difference: Women metabolize benzodiazepines slow than men
• Routes of administration
• Age:
Neonates microsomal enzymes not fully developed
Caffeine half life four days comparative to four hours in adults
•Diet:
Low protein diet and high protein diet
Protein-carbohydrate ratio
fat free diet depress cyt P 450
vitamins and minerals
grapefruit juice inhibits metabolism of many drugs
•Pregnancy: high level of steroidal hormones in pregnancy
metabolism of promazine and pethidine reduced
•Disease states: liver and kidney impairment
•Circadian rhythm: Dirunal variations or variations in the enzyme activity with light
cycle are called circadian rhythm in drug metaboism
Chronopharmacolgy
Chronokinetics
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