This document discusses various topics related to drug metabolism including prodrugs, biotransformation, enzyme induction, and enzyme inhibition. It defines a prodrug as an inactive substance that is converted to an active drug within the body by enzyme action. About 5-7% of approved drugs are prodrugs. Rationale for prodrug design includes improving formulations, enhancing absorption, changing distribution, overcoming toxicity, and extending patent life. Drug metabolism, or biotransformation, chemically modifies drugs through phase I and phase II reactions in the liver and other organs. Phase I reactions like oxidation and reduction can activate or inactivate drugs, while phase II conjugation reactions make drug metabolites more water soluble for excretion. Factors like

2. Session VI
Pro-drug, Biotransformation of drugs,
enzyme induction, enzyme inhibition
and Entero-hepatic circulation.
Aphasia
DR. GHULAM SAQULAIN
M.B.B.S., D.L.O., F.C.P.S
HEAD OF DEPARTMENT OF ENT
CAPITAL HOSPITAL,
ISLAMABAD

3. PRODRUG
 Prodrug is an inactive substance/drug that is
converted to a drug within the body by the action
of enzymes or other chemicals.
 About 5-7% of drugs approved worldwide can be
classified as prodrugs

5.  Rationale for Prodrug Design
A. Improving Formulation and Administration
B. Enhancing Permeability and Absorption
C. Changing the Distribution Profile
D. Protecting from Rapid Metabolism and Excretion
E. Overcoming Toxicity Problems
F. Managing the Life Cycle

6.  The prodrug approach is a strategy to increase the utility
of pharmacologically active compounds, because one
can optimize any of the properties as well as prolong the
commercial life cycle of potential drug
 Phosphate esters are a widely used prodrug strategy for
improving the aqueous solubility. The active parent drug
molecule is rapidly released from phosphate prodrugs by
endogenous phosphatases, such as alkaline
phosphatase.

7.  Prednisolone sodium phosphate is a classic
example of a phosphate prodrug It is a highly
water-soluble
 Also masks the unpalatable taste of prednisolone
tablets.

8. BIO TRANSFORMATION
(Drug Metabolism)
Definition
 Chemical reactions which lead to modification of drugs.
Importance of metabolism
 Termination of drug action
 Enhance excretion by transforming the drug to a less lipid
soluble, less readily reabsorbed form.

9. Organ sites of drug metabolism
 Liver (the major site).
 Intestinal Mucosa and Lumen
 Kidney
 Skin
 Lung
 Plasma

10. TYPES OF METABOLIC REACTIONS
 Phase I Reactions
 Phase II Reactions

11. Phase I reactions
 Oxidation.
 Reduction.
 Hydrolysis.
Phase II reactions
 Conjugation reactions

12. Oxidation Reactions
Microsomal oxidation (CYT-P450(.
Oxidation by cytochrome P450 enzymes
Non-microsomal oxidation.
Oxidation by soluble enzymes in cytosol or
mitochondria of cells (as oxidases and
dehydrogenases( e.g. monoamine oxidase (MAO(
and alcohol dehydrogenase.

13. Reduction reactions
 Microsomal reduction
 Non microsomal reduction
Hydrolysis
 All are non microsomal
 Drugs affected are either esters or amides
 Hydrolysis occurs by enzymes (esterases or
amidases) e.g. acetylcholine and lidocaine

14. Phase I reactions can result in
 Inactivation of drug (termination of action)
 Conversion of active drug to another active
metabolite.
 Conversion of drugs to toxic metabolites.
Paracetamol → acetaminophen hepatotoxicity
 Activation of pro-drug
 Product might undergo phase II.

15. Conjugation of metabolite (phase I) with
endogenous substance as methyl group, acetyl
group, sulphate, amino acid or glucouronic
acid to produce conjugate that is water soluble
and easily excreted.
Phase II Conjugation Reactions

16. Types of conjugation reactions
Conjugation reaction Enzyme required
glucouronide conjugation glucouronyl transferase
Acetylation N-acetyl transferase
Sulphation Sulfotransferase
Methylation methyl transferase
Amino acids conjugation

17. Phase II reactions:
 All are non microsomal except
glucouronidation
 Deficieny of glucouronyl transferase enzyme in
neonates may result into toxicity with
chloramphenicol (Gray baby syndrome).

18. Characteristics of Phase II Products
 Usually make drug Pharmacologically
inactive.
 Polar
 more water soluble.
 more readily excreted in urine.

20. Factors affecting metabolism
 Age
 Nutrition
 Genetic Variation
 Diseases
 Gender
 Degree of Protein Binding
 Enzyme Induction & inhibition
 Route of Drug Administration

21. ENZYME INDUCTION
 Enzyme induction is a process in which a
molecule (e.g. a drug) induces (i.e. initiates or
enhances) the expression of an enzyme.

22. ENZYME INHIBITION
 Enzyme inhibition can refer to the inhibition of
the expression of the enzyme by another
molecule
 Interference at the enzyme-level, basically with
how the enzyme works. This can be competitive
inhibition, uncompetitive inhibition, non-
competitive inhibition or partially competitive
inhibition.

23. Enzyme inhibition and inhibition
of metabolism
Leads to drug accumulation
and toxicity