Factors affecting metabolism of drug

1. Dr. Nilesh S. Kulkarni
Associate Professor in Pharmaceutics
PES Modern college of Pharmacy For Ladies Moshi Pune
9/21/2021 Dr. Nilesh S. Kulkarni

2. A number of factors may influence the metabolic rate of a drug. Some of them are:
1. Physicochemical properties of the drug
2. Chemical factors A) ENZYME INDUCTION
B) ENZYME INHIBITION
C) ENVIRONMENTAL CHEMICALS
3. Biological factors
A) AGE
B) DIET
C) SEX DIFFERENCE
D) SPECIES DIFFERENCE
E) STRAIN DIFFERENCE
F) ALTERED PHYSIOLOGICAL FACTORS
9/21/2021 Dr. Nilesh S. Kulkarni

3. INDUCTION AND INHIBITION OF DRUG-METABOLISING ENZYMES
The state of enzymatic systems involved in drug biotransformation represents an
important factor in pharmacokinetic and/or pharmacodynamic variability.
The changes in the state of enzymatic systems may be Qualitative and Quantitative.
QUALITATIVE CHANGES are commonly due to impairments in the state of the
enzymatic systems.
QUANTITATIVE CHANGES may evolve in two directions:
STIMULATION OF ENZYME ACTIVITY (ENZYME INDUCTION)
REDUCTION IN ENZYME ACTIVITY (ENZYME INHIBITION).
The pharmacological consequences of both phenomena are quantitative.
Induction and Inhibition leads
• Modification of intensity and/or duration of the pharmacological effect of the drug.
• Modification of t1/2 and biotransformation rate,
• Appearance of adverse reactions of overdosing, and therapeutic inefficacy.
9/21/2021 Dr. Nilesh S. Kulkarni

4. INDUCTION OF DRUG-METABOLISING ENZYMES
Induction is defined as an increase in enzyme activity associated with an increase in intracellular
enzyme concentration.
From a genetic point of view, this increase in enzymic protein is usually caused by an increase in
transcription of the associated gene.
The stimulation of enzyme activity represents increase in the concentration of a specific enzyme, due
either to an increase in its rate of synthesis, or in a decrease of its degradation rate.
The direct consequence is an accelerated/increased rate of biotransformation of both endogenous
compounds and xenobiotics, by co administration of another compound, designated as an INDUCER.
The inducer will modify the pharmacological effects of drugs
 Increase in the metabolism of the drug involved in interaction
 Decrease in the quantity of drug available for pharmacological activity).
9/21/2021 Dr. Nilesh S. Kulkarni

5. MECHANISMS OF ENZYME INDUCTION
Increase in both liver size and liver blood flow
Increase in both total and microsomal protein content
Increased stability of enzymes
Increased stability of cytochrome P-450
Decreased degradation of cytochrome P-450
Proliferation of smooth endoplasmic reticulum
CONSEQUENCES OF ENZYME INDUCTION INCLUDE
 Decrease in pharmacological activity of drugs
Increased activity where the metabolites are active
Altered physiological status due to enhanced metabolism of endogenous compounds
such as sex hormones.
9/21/2021 Dr. Nilesh S. Kulkarni

6. One of the most common types of induction is that which is substrate-dependent.
INFLUENCE OF PHENOBARBITONE ON THE METABOLISM AND DURATION OF ACTION
OF SEVERAL DRUGS.
Drugs affected (Increased Metabolism) include
Oral anticoagulants (anticoagulant effect decreased due to increased metabolism) .
Tricyclic antidepressants (antidepressant effect decreased, by the same mechanism),
Corticosteroids (corticosteroid effect decreased, by the same mechanism),
Narcotics (increased CNS depression with meperidine, increased meperidine
metabolites)
Theophyllines (theophylline effect decreased due to increased metabolism)
Muscle relaxant zoxazolamine (substantial metabolism increase, and consequently a
significant decrease in the paralysis time)
Pre-treatment with phenobarbitone has also been shown to markedly increase the
metabolism of felodipine and its pyridine analogue.
9/21/2021 Dr. Nilesh S. Kulkarni

7. POLYCYCLIC HYDROCARBON type inducers: such as 3-methyl cholanthrene and
cigarette smoke which stimulate the metabolic rate of few drugs.
Drugs for which induced metabolism due to cigarette smoking may have clinical
consequence include theophylline, caffeine, tacrine, imipramine, haloperidol,
pentazocine, propranolol, flecainide and estradiol etc.
Some drugs such as Carbamazepine, Meprobamate, Cyclophosphamide, Rifampicin
etc. stimulate their own metabolism, the phenomenon being called as AUTO-
INDUCTION OR SELF-INDUCTION.
9/21/2021 Dr. Nilesh S. Kulkarni

8. Inhibition of drug metabolism by pre-or co-administration of other drugs or xenobiotics is
a well-recognized phenomenon, with pharmacological and toxicological effects, reflected
by exacerbated pharmacodynamic activity and adverse effects of relative overdosing at
the usual therapeutic doses.
Inhibition can also take place by different pathways and mechanisms.
In principle, inhibition involves either the Blocking Of Enzymatic Synthesis, Destruction of
Pre-formed Enzymes, or Inactivation of The Enzyme by their complexation with drug
metabolites.
DIRECT CONSEQUENCE OF ENZYME INHIBITION
 Delay in the biotransformation of certain drugs, resulting thus in increased plasma
Concentrations.
 Prolongation of their pharmacological action.
INHIBITION OF DRUG-METABOLISING ENZYMES
9/21/2021 Dr. Nilesh S. Kulkarni

9. BASIC MECHANISMS OF ENZYME INHIBITION INVOLVE ONE OF THE FOLLOWING
DIRECT INHIBITION
1) Competitive inhibition
2) Non-competitive inhibition
3) Product inhibition
INDIRECT INHIBITION
1) Repression
2) Altered Physiology
9/21/2021 Dr. Nilesh S. Kulkarni

10. 3 .Biological factors
A) AGE
B) DIET
C) SEX DIFFERENCE
D) SPECIES DIFFERENCE
E) STRAIN DIFFERENCE
F) ALTERED PHYSIOLOGICAL FACTORS
9/21/2021 Dr. Nilesh S. Kulkarni

11. A) AGE
Differences in the drug metabolic rate in different age groups are mainly due to variations in
the enzyme content, enzyme activity and haemodynamics.
The ability of microsomal enzymes to metabolize drug is poor in premature infants as compared
to adults.
e.g. Caffeine has a half life of 4 days in neonates as 4 hrs in Adults.
Conjugation with sulphate is well developed (paracetamol is excreted mainly as sulphate)
but glucuronidation occurs to a very small extent. As a result, hyperbilirubinaemia
precipitates kernicterus and chloramphenicol leads to cyanosis or Gray baby syndrome in
new born. Similarly, sulphonamides cause renal toxicity and paracetamol causes
hepatotoxicity.
Children (between one year and 12 years) and older infants metabolise several drugs much
more rapidly than adults as the rate of metabolism reaches a maximum somewhere
between 6 months and 12 years of age. As a result, they require large mg/Kg doses in
comparison to adults; for example, the theophylline half-life in children is two-third of that
in adults.
9/21/2021 Dr. Nilesh S. Kulkarni

12. B) DIET
Low protein diet decreases and high protein diet increases the drug metabolising ability.
The protein-carbohydrate ratio in the diet is also important; a high ratio increases the
microsomal mixed function oxidase activity.
•Fat free diet depresses cytochrome P-450 levels since phospholipids, which are important
components of microsomes, become deficient.
•Dietary deficiency of vitamins (e.g. vitamin A, B2, B3, C and E) and minerals such as Fe,
Ca, Mg, Cu and Zn retard the metabolic activity of enzymes.
•Grapefruit inhibits metabolism of many drugs and improve their oral availability.
•Starvation results in decreased amount of glucuronides formed than under normal
conditions.
•Malnutrition in women results in enhanced metabolism of sex hormones.
•Alcohol ingestion results in a short-term decrease followed by an increase in the enzyme
activity.
9/21/2021 Dr. Nilesh S. Kulkarni

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SEX DIFFERENCE
Women metabolise benzodiazepines slowly than men and several studies show that women
on contraceptive pills metabolise a number of drugs at a slow rate.
SPECIES DIFFERENCE
Differences in drug response due to species differences are taken into account while
extrapolating the data to man.
An example of this is the metabolism of amphetamine and ephedrine. In men and
rabbit,these drugs are predominantly metabolised by oxidative deamination whereas
in rats the aromatic oxidation is the major route.
In pigs, the phenol is excreted mainly as glucuronide whereas its sulphate conjugate
dominates in cats. Certain birds utilize ornithine for conjugating aromatic acids instead
of glycine.

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STRAIN DIFFERENCES/PHARMACOGENETICS
Enzymes influencing metabolic reactions are under the genetic control.
Just as the differences in drug metabolising ability between different species are attributed
to genetics, so also are the differences observed between strains of the same animal
species. A study of inter-subject variability in drug response (due to differences in, for
example, rate of biotransformation) is called as pharmacogenetics.
The inter-subject variations in drug biotransformation may either be monogenically or
polygenically controlled. A polygenic control has been observed in studies in twins. In
identical twins (monozygotic), very little or no difference in the metabolism of
phenylbutazone, dicoumarol and antipyrine was detected but large variations were
apparent in fraternal twins (dizygotic; twins developed from two different eggs) for the
same drugs.

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ALTERED PHYSIOLOGICAL FACTORS
PREGNANCY
Maternal drug metabolising ability in animals (of both phase I and phase II reactions) is
reduced during the later stages of pregnancy.
This was suggested as due to high levels of steroid hormones in circulation during
pregnancy.
In women, the metabolism of PROMAZINE AND PETHIDINE is reduced during
pregnancy or when receiving oral contraceptives.
Higher rate of hepatic metabolism of Anticonvulsants during pregnancy is thought to
be due to INDUCTION OF DRUG METABOLISING enzymes by the CIRCULATING
PROGESTERONE.

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DISEASE STATES
Biotransformations such as GLYCINE CONJUGATION OF SALICYLATES, OXIDATION OF
VITAMIN D and HYDROLYSIS OF PROCAINE which occur in kidney, are impaired in renal
diseases.
Congestive cardiac failure and myocardial infarction which result in a decrease in the
blood flow to the liver, impair metabolism of drugs having high hepatic extraction ratio
e.g. propranolol and lidocaine.
Diabetes: GLUCURONIDATION is reduced due to DECREASED AVAILABILITY of UDPGA.

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Temporal Factors
Circadian Rhythm: Diurnal variations or variations in the enzyme activity with light cycle
is called as circadian rhythm in drug metabolism.
Enzyme Activity is Maximum during early morning (6 to 9 a.m.)
Enzyme Activity is minimum in late afternoon (2 to 5 p.m.)
It was suggested to correspond with the high and low serum levels of corticosterone (the
serum corticosterone level is dependent upon the light-dark sequence of the day).
Clinical variation in therapeutic effect of a drug at different times of the day is therefore
apparent.
The study of variations in drug response as influenced by time is called as
chronopharmacology.
Time dependent change in drug kinetics is known as chronokinetics.
Drugs such as aminopyrine, hexobarbital and imipramine showed diurnal variations in
rats.

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Xenobiotics/
drugs
Reactive
Metabolites
Reactive
Metabolites
Free Radical
Electrophiles
Peroxidation
/ Oxidative
degenration of cells
Covalent binding
to tissues
Tissue
Toxicity
BIOACTIVATION AND TISSUE TOXICITY

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ELECTROPHILES
Paracetamol
N-hydroxylation further loss of
Water molecule
Imidoquinone
Derivative
(Electrophile)
Conjugation
with GSH
Covalent binding to
liver tissues when
GSH is depleted.