Phase I Vs Phase II Drug metabolism and factors affectiing drug metabolism. Enzyme induction, Enzyme inhibitor, physicochemical properties wthich acan affect the drug metabolism

1. PHASE –I DRUG METABOLISM VS PHASE II DRUG METABOLISM
&
FACTORS AFFECTING DRUG METABOLISM
Mrs. Asha Suryawanshi
Asst. Professor
M. Pharm(Pharmaceutical Chemistry)
SDDVCOP & RC New Panvel

2. PHASE I DRUG METABOLISM
VS
PHASE II DRUG METABOLISM

4. MeDcheMstudy
4
FACTORS AFFECTING DRUG METABOLISM

5. Various physiological and pathological factors can also affect drug metabolism.
Physiological factors that can influence drug metabolism include age,
individual variation (e.g., pharmacogenetics), enterohepatic circulation, nutrition,
intestinal flora, or sex differences.
In general, anything that increases the rate of metabolism (e.g., enzyme
induction) of a pharmacologically active metabolite will decrease the duration
and intensity of the drug action.
The opposite is also true (e.g., enzyme inhibition). However, in cases where an
enzyme is responsible for metabolizing a prodrug into a drug, enzyme induction
can speed up this conversion and increase drug levels, potentially causing toxicity

6. MeDcheMstudy
6
FACTORS AFFECTING DRUG METABOLISM
FACTORS AFFECTING DRUG METABOLISM
CHEMICAL FACTORS BIOLOGICAL FACTOR
PHYSIOLOGICOCHEMIC
AL PROPERTIES OF
DRUG
Enzyme Induction
Enzyme Inhibition
Age
Diet
Sex Difference
Species Difference
Strain Difference
Altered physiological
properties

7. MeDcheMstudy
7
Chemical factor
A) Enzyme induction
The phenomenon of increased drug metabolism ability of enzymes by several
drug and chemicals is call as enzyme induction and the agents which bring
about such an effect are called enzyme inducer.
Mechanism :
•Increase in both liver size and liver blood.
• Increase in both total and microsomal protein content.
•Increased stability of the enzymes
•Increased stability of cytochrome P-450
•Decreased degradation of cytochrome P-450
•Proliferation of smooth endoplasmic reticulum
Example:

8. MeDcheMstudy
8
B) Enzyme Inhibition
A decease in the drug metabolizing ability of an enzyme is called a Enzyme Inhibition.
The process of inhibition may be direct or indirect inhibition.
I) Direct inhibition:
It may result from interaction at the enzymic site, the net outcome being a change in
enzyme activity.
It can occur by one of the following mechanism:
Competitive inhibition: Occurs when structurally similar compounds complete for
the same site on an enzyme.
Non Competitive inhibition: Occurs when structurally unrelated compounds interacts with
the enzyme and prevents the metabolisms of drug
Product inhibition: occur when the metabolic product complete with the substrate for the
same enzyme

9. MeDcheMstudy
9
II) Indirect inhibition:
It is caused by one of the following mechanism:
Repression: It may be due to fail in the rate of enzyme synthesis or rise in the
rate of enzyme degradation
Altered Physiology: It may be due to nutritional deficiency or hormonal
imbalance

10. MeDcheMstudy
10
BIOLOGICAL FACTOR
a) Age:
The drug metabolite rate in the different
age groups differs.
 In neonates ( up to 2 month) and in infant (2 months to 1 yr), the
microsomal
enzyme system is not fully developed, so drug metabolized slowly.
Eg. Caffeine has half life of 4 days in neonates in comparison to 4 hrs in
adult
 Children (between 1 yr and 12 years)metabolize several drugs much
more rapidly than adults as rate of metabolism reaches a maximum.
 In elderly person, the liver size is reduced, the microsomal enzyme
activity is decreased and hepatic blood flow also declines as a result of
reduced output, all of which contributes to decreased metabolism drugs

11. MeDcheMstudy
11
b) Diet:
The enzyme content and activity is altered by number a
number of dietatory component.
Low protein diet decreases and high protein increases the drug metabolism. As enzyme
synthesis is promoted by protein diet.
Free fat diet decrease cytochrome P-450 level since phospholipids, Which are
important components of microsomes become deficient.
Grape fruit inhibits metabolism of many drugs and improve their oral bioavailability.
Starvation results in decreased amount of glucuronides formed than under normal
conditions.
c) Gender difference:
Drug metabolism rate in men and women is difference may be due to sex hormone.
In human studies have shown that women metabolize benzodiazepines slowly than men

12. MeDcheMstudy
12
d) Species difference:
•Species difference is observed in phase I and phase II reactions, both qualitative
and quantitative variations in the enzyme and their activity have been observed.
• Human liver contains less cytochrome P-450/gm of tissue than do the liver of
other species.
For Eg.
 Rat liver contains 30 to 50 nmol/g of cytochrome P-450 whereas
in human liver contains 10 to 20 nmol/g of cytochrome P-450 .
 In pig, the phenol is excreted mainly as grucuronide whereas its sulphate
conjugate dominate in cat

13. d) Strain difference:
Just as difference in drug metabolizing ability between different species is attributed
to genetics, the differences are obserevd between strains of same species also. It may
be studies under two headings:
i) Pharmacogenetics:
A study of inter-subject variability in drug response is called as pharmacogenetics
Polygenetic controle is obsereved in twins.
In identical twins (monozygotic) is very little or no difference in metabolism in
various drug but large variation were observed in fraternal ( dizygotic)

14. MeDcheMstudy
14
ii) Ethic Variations:
Difference obsereved in the metabolism of drug among difference races are called as
ethic variations.
Such variation may be monomorphic or polymorphic.
Eg. Approximately equal percent of slow and rapid acetylators are found among whites
and black whereas the slow acetylators dominate Japanese and Eskimo population

15. MeDcheMstudy
15
Physicochemical property of drug
Physicochemical property of drug can be affect the drug metabolism.
•Molecular size & shape
•pKa value
•Acidity/ Basicity
•Lipophilicy
•Steric and electronic characteristics
As drug influence in interaction with the active site of enzyme and the
metabolism to which it is subjected.

16. MeDcheMstudy
16

17. MeDcheMstudy
17