This document discusses factors that affect drug metabolism in the body. It defines drug metabolism as the biochemical modification of pharmaceuticals through enzyme activity. Several chemical and biological factors can influence this metabolic process. Chemically, a drug's metabolism may be induced or inhibited by other substances through effects on enzyme activity. Biologically, factors like age, diet, sex, species and physiological state can impact the levels and function of drug-metabolizing enzymes. Understanding how these factors interplay is important for predicting a drug's pharmacokinetic properties and therapeutic effects.

1. Biopharmaceutical
Factors affecting
Metabolism
-Sajan Maharjan
M.Pharm (1st Sem.)
18/02/2014
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2. drug gets into bloodstream
gets to site of action
is “changed” so that it can be excreted
leaves the body
Definition
Drug metabolism is a biochemical modification of
pharmaceutical substances usually through specialized enzymatic
activity.
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3. Metabolite A
Inactive
Enz. A
Enz. B
Metabolite B
Active
Enz. C
Metabolite C
Toxic
Drug
Enz. D
Metabolite D
Undetectable
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4. Mechanism
Drugs
Highly lipophilic
lipophilic
Polar
Hydrophilic
Accumulation
(Storage in body tissues
Phase-1 Metabolism
(Bioactivation or Inactivation)
Polar
Phase-II Metabolism
(Inactivation)
Hydrophilic
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Execretion
(Renal or biliary)
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5. Factors affecting Drug Metabolism
Chemical Factors
Biological Factors
Enzyme induction
Age
Enzyme inhibition
Physicochemical
properties of drug
Diet
Sex differences
Species differences
Strain differences
Altered Physiological factors
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6. Chemical Factors
Enzyme induction
It is the phenomenon of incresed drug metabolising ability of
enzymes by several drugs and chemicals.
Consequences
Active
Metabolites
Inactive
Metabolites
Increased
pharmacological
activity or TOXICITY
Decreased
pharmacological
activity
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Altered
physiological
status due to
enhanced
metabolism of
compounds
Eg: sex
hormones
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7. Examples of enzyme induction
Oral
Contraceptive
Steroids
CYP3A4
Inactive, Excreted
Induction
Rifampin
Acetaminophen
CYP2E1
p-Quinone Imine (Toxic)
Induction
Ethanol
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8. Enzyme inhibition
It is a decrease in the drug metabolising activity of an enzyme.
The process of inhibition may be:
Direct inhibition
Indirect inhibition
Repression
Decrease in
the enzyme
content
Competitive
inhibition
Altered physiology
Due to nutritional
deficiency or
hormonal
imbalance
Non-competitive
inhibition
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9. Examples of enzyme inhibition
Terfenadine
CYP3A4
Active Antihistamine
Inhibition
Erythromycin
Ketoconazole
Consequences of Inhibition
• Increase in the plasma concentration of parent drug
• Reduction in metabolite concentration
• Exaggerated and prolonged pharmacological effects
• Increased likelihood of drug-induced toxicity
Enzyme inhibition is more important clinically than enzyme
induction esp. for drugs with narrow therapeutic index.
Eg: anticoagulants,antiepileptics,hypoglycemias,etc.
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10. Biological factors
Age
Neonates and infants
(upto 1 year)
Microsomal
enzyme system is
not fully
developed
Many drugs metabolised
slowly
Half life of caffeine
In neonates: 4 days
In adults: 4 hours
Children (1 to 12 years)
Elderly
Reduced
liver size
Rate of
metabolism
reaches maximum
Require large mg/kg
dose than adults
Half life of theophylline
in children is 2/3rd of that
in adults
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Reduced
hepatic
blood flow
Reduced
enzyme
activity
Decreased metabolism
of drugs
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11. Diet
Enzyme content and activity is altered by dietary components
Protein diet
Fat free diet
grapefruit
Vitamins and minerals
Vitamin A, B2,B3,C & E
Enzyme
synthesis is
promoted
Increased drug
metabolising
activity
Depresses
cytochrome
P-450 levels
Decreased drug
metabolising
activity
Inhibit
metabolism
of some
drugs
Eg:
Terfenadine
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Ca, Fe, Mg & ZN
Retard metabolic
activity of enzymes
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12. Sex difference
 Responsiveness to certain drugs is different for men and women.
 Such variations are generally observed following puberty. So,
sex related differences in the rate of metabolism could probably
be due to sex hormones.
Examples
Studies in animals
Male rats
have greater
drug
metabolising
capacity
Studies in humans
Women metabolise
benzodiazepines
slowly than men
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Women on
contraceptive
pills metabolise
some drugs
slowly
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13. Species differences
Differences are mainly quantitative but there are some qualitative
differences too
Examples
In Phase-I reactions
In Phase-II reactions
Metabolism of
amphetamine and
ephedrine
By aromatic
oxidation
By oxidative
deamination
• Variations are mainly qualitative.
Glucuronide conjugation is an
important route of metabolism in
mammals, birds, reptiles, and
amphibians, but not in fish.
In mammals, cats lack the ability to
conjugate phenols with Glucuronic
acid but it dominates in pigs
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14. Strain differences
Pharmacogenetics
(Study of intersubject variability in
drug response)
Ethnic variations
(variation among different races)
Acetylation
of isoniazid
Metabolism of
phenylbutazone,
antipyrine
Whites and blacks
In monozygotic twins
Very little
or No
difference
In dizygotic twins
Large
difference
Equal percent
of slow and
rapid
acetylators
found
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Japanese and Eskimo
Slow
acetylators
dominate
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15. Altered Physiological factors
Pregnancy
High levels
of steroid
hormones
Maternal drug
metabolising
ability is reduced
Diseased states
Liver disease
(hepatitis,
jaundice etc)
Reduction in
hepatic drug
metabolising
ability
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Renal
disease
Oxidation of
Vit.D.
Conjugation
of salicylates
are impaired
CCF,
MI
Decrease in
blood flow
to liver
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16. Physicochemical properties of drug
Molecular
size and
shape
pKa
Acidity/
Basicity
lipophilicity
Steric and
electronic
characters
Interaction with the active site of
enzyme
Affects metabolic
process
Such an interrelationship is not clearly understood
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