Drug Metabolism
Contents
• Drug metabolism
• Functions of biotransformations
• Sites of biotransformation
• Drug metabolizing enzymes
• Factors affecting drug metabolism
Intended
learning outcomes
At the end of this
lecture, student will be able to:
• Describe the drug metabolism.
• Explain the sites involved in biotransformation.
• List out the enzymes involved in drug metabolism
Metabolism or Biotransformation
• Metabolism is an essential pharmacokinetic process, which
renders lipid soluble and non-polar compounds to water soluble and polar
compounds so that they are excreted by various processes.
• The term metabolism is commonly used probably because
products of drug transformation are called metabolites.
• This is because only water-soluble substances undergo
excretion, whereas lipid soluble substances are passively reabsorbed from renal
or extra renal excretory sites into the blood by virtue of their lipophilicity.
• Metabolism is a necessary biological process that limits
the life of a substance in the body.
• Biotransformation:
It is a specific term used for chemical transformation of xenobiotics in the
body/living organism.
A series of enzyme- catalyzed processes—that alters the
physiochemical properties of foreign chemicals (drug/xenobiotics) from those
that favor absorption across biological membranes (lipophilicity) to those
favoring elimination in urine or bile (hydrophilicity )
• Metabolism: It
is a general term used for chemical transformation of xenobiotics and
endogenous nutrients (e.g., proteins, carbohydrates and fats) within or outside
the body.
• Xenobiotics:
These are all chemical substances that are not nutrient for body (foreign to
body) and which enter the body through ingestion, inhalation or dermal
exposure.
They include:
drugs, industrial chemicals, pesticides, pollutants, plant and animal toxins,
etc.
Functions of Biotransformation
• It causes conversion of an active drug to inactive or less
active metabolite(s) called as pharmacological inactivation.
• It causes conversion of an active to more active
metabolite(s) called as bioactivation.
• It causes conversion of an inactive to more active toxic
metabolite(s) called as lethal synthesis.
• It causes conversion of an inactive drug (pro-drug) to
active metabolite(s) called as pharmacological activation
• It causes conversion of an active drug to equally active
metabolite(s) (no change in pharmacological activity)
• It causes conversion of an active drug to active
metabolite(s) having entirely different pharmacological activity (change in
pharmacological activity)
Site/Organs of drug metabolism
The major site of drug metabolism is the liver (microsomal
enzyme systems of hepatocytes)
Secondary organs of biotransformation
– Kidney (proximal tubule)
– Lungs (type II cells)
– Skin (epithelial cells)
– Intestines
– Plasma
– Nervous tissue (brain)
– Testes (Sertoli cells)
Liver
• The primary site for metabolism of almost all drugs
because it is relatively rich in a large variety of metabolising enzymes.
• Metabolism by organs other than liver (called as
extra-hepatic metabolism) is of lesser importance because lower level of
metabolising enzymes is present in such tissues.
• Within a given cell, most drug metabolising activity is
found in the smooth endoplasmic reticulum and the cytosol.
• Drug metabolism can also occur in mitochondria, nuclear
envelope and plasma membrane.
• A few drugs are also metabolised by non-enzymatic means
called as non-enzymatic metabolism.
• For example, atracurium, a neuromuscular blocking drug, is
inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman
elimination) in addition to that by pseudocholine esterase enzyme.
Subcellular locations of metabolising enzymes
Endoplasmic Reticulum (microsomes):
The primary location for the metabolizing enzymes.
(a) Phase I:
cytochrome P450, flavin-containing monooxygenase, aldehyde oxidase,
carboxylesterase, epoxide hydrolase, prostaglandin synthase, esterase.
(b) Phase II:
uridine diphosphate-glucuronosyltransferase, glutathione S-transferase, amino
acid conjugating enzymes.
Cytosol (the soluble fraction of the cytoplasm):
Many water-soluble enzymes.
(a) Phase I:
alcohol dehydrogenase, aldehyde reductase, aldehyde dehydrogenase, epoxide
hydrolase, esterase.
(b) Phase II:
sulfotransferase, glutathione S-transferase, N-acetyl transferase, catechol
0-methyl transferase, amino acid conjugating enzymes.
Mitochondria
Phase I:
monoamine oxidase, aldehyde dehydrogenase, cytochrome P450.
Phase II:
N-acetyl transferase, amino acid conjugating enzymes.
Lysosomes
Phase I:
peptidase.
Nucleus
Phase II: uridine
diphosphate-glucuronosyl transferase (nuclear membrane of enterocytes).
Drug Metabolising Enzymes
• A number of enzymes in animals are capable of metabolising
drugs. These enzymes are located mainly in the liver, but may also be present
in other organs like lungs, kidneys, intestine, brain, plasma, etc.
• The drug metabolising enzymes can be broadly divided into two groups: microsomal and
non-microsomal enzymes.
• Microsomal enzymes:
The endoplasmic reticulum (especially smooth endoplasmic reticulum) of
liver and other tissues contain a large variety of enzymes, together called
microsomal enzymes
• microsomes are minute spherical vesicles derived from
endoplasmic reticulum after disruption
of cells by centrifugation, enzymes present in
microsomes are called microsomal enzymes.
• They catalyse glucuronide conjugation, most oxidative
reactions, and some reductive and hydrolytic reactions.
• The monooxygenases, glucronyl transferase etc are important
microsomal enzymes.
• Non-microsomal
enzymes: Enzymes occurring in organelles/sites other than endoplasmic
reticulum (microsomes) are called non-microsomal enzymes.
• These are usually present in the cytoplasm, mitochondria,
etc. and occur mainly in the liver, Gl tract, plasma and other tissues.
• They are usually non-specific enzymes that catalyse few
oxidative reactions, a number of
reductive and hydrolytic reactions, and all conjugative reactions other than
glucuronidation.
• None of the non-microsomal enzymes involved in drug
biotransformation is known to be inducible.
Factors Affecting Drug Metabolism
1. Species differences: eg in phenyl butazone, procaine and
barbiturates.
2. Genetic differences – variation exist.
3. Age of animal –feeble in fetus, aged, newborn.
4. Sex: under the influence of sex hormones.
5. Nutrition: starvation and malnutrition
6. Pathological conditions: Liver/Kidney dysfunction
SUMMARY
• Metabolism is an essential pharmacokinetic process, which
renders lipid soluble and non-polar compounds to water soluble and polar
compounds so that they are excreted by various processes.
• The major site of drug metabolism is the liver.
• Within a given cell, most drug metabolising activity is
found in the smooth endoplasmic reticulum and the cytosol.
• Drug metabolism can also occur in mitochondria, nuclear
envelope and plasma membrane.
• Enzymes occurring in organelles/sites other than
endoplasmic reticulum (microsomes) are called non-microsomal enzymes.
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