Lecture 14 Prodrug, biotransformatiion, enzyme induction and inhibition
Pro-drug, Biotransformation of drugs,
enzyme induction, enzyme inhibition
and Entero-hepatic circulation.
DR. GHULAM SAQULAIN
M.B.B.S., D.L.O., F.C.P.S
HEAD OF DEPARTMENT OF ENT
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
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
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
Prednisolone sodium phosphate is a classic
example of a phosphate prodrug It is a highly
Also masks the unpalatable taste of prednisolone
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.
Organ sites of drug metabolism
Liver (the major site).
Intestinal Mucosa and Lumen
TYPES OF METABOLIC REACTIONS
Phase I Reactions
Phase II Reactions
Phase I reactions
Phase II reactions
Microsomal oxidation (CYT-P450(.
Oxidation by cytochrome P450 enzymes
Oxidation by soluble enzymes in cytosol or
mitochondria of cells (as oxidases and
dehydrogenases( e.g. monoamine oxidase (MAO(
and alcohol dehydrogenase.
Non microsomal reduction
All are non microsomal
Drugs affected are either esters or amides
Hydrolysis occurs by enzymes (esterases or
amidases) e.g. acetylcholine and lidocaine
Phase I reactions can result in
Inactivation of drug (termination of action)
Conversion of active drug to another active
Conversion of drugs to toxic metabolites.
Paracetamol → acetaminophen hepatotoxicity
Activation of pro-drug
Product might undergo phase II.
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
Phase II reactions:
All are non microsomal except
Deficieny of glucouronyl transferase enzyme in
neonates may result into toxicity with
chloramphenicol (Gray baby syndrome).
Characteristics of Phase II Products
Usually make drug Pharmacologically
more water soluble.
more readily excreted in urine.
Factors affecting metabolism
Degree of Protein Binding
Enzyme Induction & inhibition
Route of Drug Administration
Enzyme induction is a process in which a
molecule (e.g. a drug) induces (i.e. initiates or
enhances) the expression of an enzyme.
Enzyme inhibition can refer to the inhibition of
the expression of the enzyme by another
Interference at the enzyme-level, basically with
how the enzyme works. This can be competitive
inhibition, uncompetitive inhibition, non-
competitive inhibition or partially competitive
Enzyme inhibition and inhibition
Leads to drug accumulation