It refers to a series of chemical alterations of a drug by enzymatic activity occur within the body.
Sites of Biotransformation:
Liver:
In spite of the fact that every tissue
has capacity to metabolize drugs, the
liver is the basic organ of drug metabolism. After oral administration, Some
drugs like Isoproterenol, meperidine, pentazocine,
morphine are absorbed from small intestine but go through extensive metabolism
in liver by the cytochrome P450 enzymatic system. Drugs are converted from fat
soluble to water soluble substances that can be excreted in the urine and bile.
GIT:
Some orally administered medicines(drugs) similar as
clonazepam, chlorpromazine, cyclosporine are well metabolized in intestine than
in liver, but others similar as midazolam suffer 50 intestinal metabolism. Some
medicines are metabolised by intestinal microorganisms, gastric acids and
digestive enzymes, for illustration penicillin, insulin and epinephrine.
Other sites:
Lungs, kidneys, adrenal glands and
skin.
Phases of Biotransformation:
- Phase I reactions (O.R.H)
- Phase II reactions
Phase I Reactions (O.R.H)
What is ORH?
- Oxidation
- Reduction
- Hydrolysis
Phase II Reactions
- Conjugation
Phase I Reactions:
Phase I reactions is also called
enzymatic transformation.
These reactions change drug molecules
into more polar water soluble molecules by establishing or unmasking a polar
functional group, such as ,-OH, -NH2, -SH. Phase I metabolism may increase,
decrease or leave unaltered the pharmacological activity of drugs.
Oxidation:
It involves addition of oxygen or
removal of hydrogen from the drug.
Cytochrome P-450 dependent (microsomal mixed function oxidase) oxidation:
These reactions are brought about by
an enzyme system known as mixed function oxygenase which is located in
lipophilic membrane of smooth endoplasmic reticulum of liver and other tissues,
it has two components namely NADPH-cytochrome P-450 reductase and cytochrome P-450.
Reaction Example:
- Aromatic hydroxylation
For example; propranolol, warfarin
- Aliphatic hydroxylation
For example; digitoxin, ibuprofen
- Epoxidation
- Oxidative dealkylation
For example; paracetamol / acetaminophen
- S-oxidation
For example; cimitidine
- N-oxidation
- Deamination
For example; Diazepam
- Desulfuration
For example; thiopental
- Dechlorination
Induction and inhibition of cytochrome P450 drug metabolizing enzymes
Enzyme Induction:
Some drugs induce cytochrome P-450
drug metabolizing enzymes by increasing their synthesis or reducing their
degradation, as a result accelerating the metabolism of certain drugs that can
lead to their decreased pharmacological effects.
Enzyme inhibition:
Some drugs inhibit cytochrome P450
drug metabolizing enzymes, as a result decreasing the metabolism of certain
drugs thereby increasing their pharmacological effects.
Drugs inducing and inhibiting Cytochrome P450
Important inducers:
- Barbiturates
- Rifampicin
- Ethanol
- Phenylbutazone
- Phenytoin
- Carbamazepine
Important inhibitors:
- Cimitidine
- Allopurinol
- Isoniazid (INH)
- Chloramphenicol
- Ketoconazole
- Disulfiram
Cytochrome P-450 independent (non-microsomal) oxidation:
This involves drug oxidation by
enzymes found in cytosol or mitochondria of cells.
Reaction examples:
- Alcohol dehydrogenase converts Ethanol to acetaldehyde.
- Aldehyde dehydrogenase converts acetaldehyde to acetate.
- Xanthine oxidase change hypoxanthine to xanthine and xanthine to uric acid.
- Tyrosine hydroxylase converts tyrosine to dopa.
- Monoamine oxidase metabolizes catecholamines and serotonin.
Types of mono-amine oxidase (MAO) enzymes
MAO type A:
Present anywhere but mainly in liver,
metabolized norepinephrine, serotonin and tyramine.
MAO Type B:
Present mainly in brain, metabolized
dopamine.
Reduction:
It occurs in both microsomal and non
microsomal metabolizing systems.
Reaction examples:
- Azo reductions
- Nitro reductions
- Carbonyl reductions
Hydrolysis:
It involves non microsomal hydrolase
present in various body systems including plasma.
Reactions examples:
- Esterases
- Peptidases
- Phosphatases
- Amides
Phase II Reactions (Conjugation):
These responses do when phase I
metabolities aren't sufficiently polar and can not be readily excreted. In
these responses, an endogenous substance( for illustration glucuronic acid,
sulphuric acid, acetic acid or amino acid) combines with recently established
functional group to form a largely polar conjugate that can be readily
excreted.
Reaction examples:
- Glucuronidation
For example; morphine, paracetamol and
diazepam
- Acetylation
For example; sulfonamides and clonazepam
- Glutathione Conjugation
For example; ethacrynic acid
- Glycine Conjugation
For example; salicylic acid
- Water Conjugation
For example; carbamazepine
- Methylation
For example; dopamine and norepinephrine
Factors affecting drug metabolism
(For memorization of these factors remember RCD-GAS-DD)
Route of administration:
Oral route can result in extensive
first pass effect.
Chemical properties of drugs:
Certain drugs may stimulate or inhibit
the metabolism of drugs.
Diet:
Starvation depletes glycine and alters
glycine conjugation.
Genetic factors:
Such as Acetylation of Isoniazid is
under genetic control.
Age:
Liver cannot detoxify chloramphenicol (an
antibacterial agent, inhibitor of protein synthesis in bacteria) in neonates thereby
causing grey-baby syndrome.
Sex or gender:
Young males are more susceptible to
sedation from barbiturates than females.
Dosage:
Toxic doses deplete enzymes.
Diseases:
Liver diseases decrease drug
metabolism and kidney diseases decrease excretion of drugs.
Learn more
What is biotransformation?
What is drug metabolism?
There are how many sites of
biotransformation?
Sites of biotransformation
There are how many phases of
biotransformation?
Phases of biotransformation
What is phase I metabolism?
What is phase I reactions?
What is ORH?
What is phase II metabolism?
What is phase II reactions?
What is enzymatic transformation?
What is oxidation in metabolism?
What is Cytochrome P450 dependent oxidation
?
What is microsomal mixed function
oxidase oxidation?
Reaction examples of Cytochrome P450 dependent
oxidation
Induction and inhibition of cytochrome
P450 drug metabolizing enzymes
Enzyme Induction
Enzyme inhibition
Drugs inducing and inhibiting
Cytochrome P450
Important inducers of cytochrome P450
Important inhibitors of cytochrome
P450
What is cytochrome P450 independent oxidation?
What is non-microsomal oxidation?
Reaction examples of cytochrome P450 independent
oxidation
There are how many types of mono amine
oxidase enzymes
Types of mono-amine oxidase enzymes
What is MAO?
Mono-amine oxidase type A
MAO type A
Mono-amine oxidase type B
MAO type B
What is reduction in metabolism?
Reaction examples of reduction in metabolism
What is Hydrolysis in metabolism
Reaction examples of Hydrolysis in metabolism
What is phase II reactions?
What is Conjugation?
Reaction examples of phase II reactions
Factors affecting drug metabolism
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