IT COVERS VARIOUS PHASE I AND PHASE II REACTIONS OF DRUG METABOLISM.

1. DRUG METABOLISM
PRINCIPLES
PHASE I & II
REACTION
Ms. Navdha N. Soni
Asst. Professor
L.J. Institute of Pharmacy, Ahmedabad
1

2. DRUG METABOLISM
Drug undergoes metabolism which leads to loss of its physiological activity and an
increase in the polarity and water solubility of the drug which results in more rapid
elimination of the metabolite.
The metabolism of any drug is generally characterized by two phases of reaction
q Biotransformation (Metabolic Transformation)
q Conjugation
The primary site for drug metabolism is liver; others are kidney, intestine, lungs and
plasma.
Most drugs are metabolized, at least to some extent by both phases of metabolism.
E.g. Acetyl salicylic acid while some drugs are considered biochemically inert as they
have been excreted unchanged i.e. without any metabolic transformation E.g.
Barbitone
2

3. DRUG METABOLISM
3

4. PHASE I REACTION (NON-SYNTHETIC PHASE)
q It is called Functionalization
Reaction
q Introduction of functional
groups such as -OH, -NH2, -
SH, -COOH into the
compound to produce more
water-soluble compound.
q It involves oxidation,
Reduction and Hydrolysis.
4

5. 1. OXIDATIVE REACTION (OXIDATION)
q N- hydroxylation of Dapsone:
q When Dapsone undergoes oxidation reaction with
the help of CYP enzyme and it converts into
hydroxy Dapsone.
q It further undergoes conjugation reaction produce
nitroso compound which can be easily eliminated.
5

6. 1. OXIDATIVE REACTION (OXIDATION)
N oxidation of
nicotine:
S oxidation of
chlorpromazine:
6

7. 1. OXIDATIVE REACTION (OXIDATION)
7

8. ROLE OF CYTOCHROME P450 MONOOXYGENASES
IN OXIDATIVE BIOTRANSFORMATIONS
q General stoichiometry that describes the oxidation of many xenobiotics (R-H) to
their corresponding oxidized metabolites (R-OH) is given by the following equation
q RH + NADPH + O2 + H+ ROH + NADP+ + H2O
q The enzyme systems carrying out this biotransformation are referred to as mixed-
function oxidase or monooxygenases.
q The reaction requires both molecular oxygen and the reducing agent NADPH.
q During this oxidative process, one atom of molecular oxygen is introduced into the
substrate R-H to form R-OH and the other oxygen atom is incorporated into water.
q CYP enzymes, which are responsible for transferring an oxygen atom to the
substrate R-H.
8

9. q The CYP enzymes are heme proteins.
q The heme portion is an iron-containing porphyrin called protoporphyrin IX, and the
protein portion is called the apoprotein.
q CYP is found in high concentrations in the liver, the major organ involved in the
metabolism of xenobiotics.
q The presence of this enzyme in many other tissues (e.g., lung, kidney, intestine, skin,
placenta, adrenal cortex) shows that these tissues have drug-oxidizing capability
too.
q The CYP monooxygenases are located in the endoplasmic reticulum. Many of the
Cytochrome enzymes that are responsible for the biosynthesis of steroidal
hormones and metabolism of certain vitamins.
ROLE OF CYTOCHROME P450 MONOOXYGENASES
IN OXIDATIVE BIOTRANSFORMATIONS
9

10. ROLE OF CYTOCHROME P450 MONOOXYGENASES
IN OXIDATIVE BIOTRANSFORMATIONS
10

11. 2. REDUCTION
q Reductive processes play an important role in the metabolism of many compounds
containing carbonyl, nitro, and azo groups.
q Bio-reduction of Carbonyl compounds generates alcohol derivatives.
q Nitro and azo reductions lead to amino derivatives.
q The hydroxyl and amino moieties of the metabolites are much more susceptible to
conjugation than the functional groups of the parent compounds.
q Hence, reductive process facilitate drug elimination
11

12. 3. HYDROLYSIS
q The metabolism of ester and amide
linkages in many drugs is catalysed by
hydrolytic enzymes present in various
tissues and in plasma.
q The metabolic products formed generally
are polar and functionally more susceptible
to conjugation and excretion than the
parent ester or amide drugs.
q Hydrolysis is a major biotransformation
pathway for drugs containing an ester
functionality
12

13. PHASE II REACTION (CONJUGATION)
Various phase II or conjugation reactions can convert these metabolites to more polar
and water-soluble products.
Many conjugative enzymes accomplish this objective by attaching small, polar, and
ionizable endogenous molecules, such as glucuronic acid, sulphate, glycine, and
glutamine, to the phase I metabolite or parent xenobiotic.
The resulting conjugated products are relatively water soluble and readily
excretable.
Other phase II reactions, such as glucuronidation, methylation, acetylation, sulphate
conjugation and glutathione an mercaptopuric conjugates.
13

14. 1. GLUCURONIDATION REACTION
q It involves metabolite conjugation
with activated form of glucuronic
acid.
q Molecule associated with alcoholic
hydroxyl, phenolic hydroxyl and
carboxylic acid undergoes
glucuronidation.
14

15. 2. SULPHATE CONJUGATION
q It is very fewer common drugs having
hydroxy group, phenol & aromatic
amines undergoes sulphate conjugation
with the help of sulphotransferase
enzyme.
q Most of steroidal drugs undergo
metabolism by this reaction.
Estrone
Sulphate Conjugate
15

16. 3. METHYLATION
q Most of the endogenous amines undergo methylation with the help of
methyltransferase enzyme. E.g. COMT
16

17. 4. ACETYLATION
q Acetylation involves conjugation with acetyl Co A using the enzyme acetyl transferase which is
present in liver, spleen and RBC.
q Drugs containing amino or hydrazine functional group undergoes acetylation.
q E.g. Acetylation of Isoniazid
17

18. 5. CONJUGATION WITH AMINO ACID
q This is the most important route n conjugation of rug for elimination.
q Glycine is the most common amino acid forms water soluble ionic conjugates with
aromatic, aliphatic and heterocyclic carboxylic acid and their derivatives.
18

19. GLUTATHIONE AND MERCAPTOPURIC CONJUGATION
q It is important in elimination of polyclinic phenols and halides.
q Mainly it is catalyzed by enzyme glutathione transferase.
19

20. FACTORS AFFECTING DRUG METABOLISM
A large no. of physical, chemical, biological factors affects metabolism of drug.
q Physico-chemical properties of drug molecule:
Size, shape, acidity, basicity, lipophilic character, solubility, pKa value of drug
molecule affect its metabolism.
q Chemical factors:
Various chemical affects drug metabolism presence of enzyme inducers and
inhibitors alter the action of drug metabolizing enzyme.
Enzyme Induction (Chemical inducers):
➩ These are the chemicals which increases the activity of enzyme which causes
metabolism. For eg. 3 methyl cholanthrene and cigarette smoke increases
metabolism of some drug.
20

21. FACTORS AFFECTING DRUG METABOLISM
➩ Alcohol increases metabolism of coumarines, phenytoins and barbiturates increases
metabolism of oral contraceptives and cortisol.
➩ Various drugs like rifampicin and isoniazides stimulates their own metabolism – self
induction .
Enzyme inhibitors:
➩ These are the chemical which decreases the activity of enzyme which causes
metabolism.
➩ Inhibition may be direct, comparative, non comparative & indirect.
➩ MAO inhibitors decreases the metabolism of barbiturates & coumarins decreases
the biotransformation of phenytoin.
21

22. q Environmental factors: Various environmental factors like temperature, pressure,
atmospheric humidity affect drug metabolism.
q Biological factors: Various biological factors which affects metabolism of drug are
age of patient, diet, gender, altered physiological state like pregnancy, disease
and hormonal imbalance etc.
q Pharmacodynamic factors: Dose, frequency, route of administration, tissue
distribution and protein binding of drug affect the metabolism.
q Stereochemical aspects
FACTORS AFFECTING DRUG METABOLISM
22

23. THANK YOU
23