This is a detailed presentation of drug metabolism and has a clear concept on pro drug.

1. Welcome
To Our Presentation

2. Our Presentation Topic Is:
Drug metabolism and The concept of pro-
drug
Course name : Medicinal chemistry-I
Course code: BPH-232
Course teacher: Md. Abdullah Aziz

3. Name Of Our Group Members:
Name ID
Bisshojit Biswas BPH 051 06831

4. Drug Metabolism: Definition
Drug metabolism also known as xenobiotic
metabolism is the biochemical modification of
pharmacological substances or xenobiotics
respectively by living organisms, usually through
specialized enzymatic systems. Drug metabolism
often converts lipophilic chemical compounds into
more readily excreted hydrophilic products. The rate
of metabolism determines the duration and intensity
of drug’s pharmacological action.
Xenobiotic came from the Greek word xenos mean
“stranger” and biotic mean “related to living beings”.

5. Drug Metabolism: (Xenobiotic
Metabolism)
Xenobiotic metabolism is the set of metabolic
pathways that modify the chemical structure of
xenobiotics, which are compounds foreign to an
organism's normal biochemistry, such as drugs and
poisons.
These pathways are a form of biotransformation
present in all major groups of organisms, and
considered to be of ancient. These pathways are of
particular interest in medicine as part of drug
metabolism and as a factor contributing to multidrug
resistance in infectious diseases and cancer
chemotherapy.

6. Drug Metabolism: Phases
There are three phases of drug metabolism.
They are-
 Phase I: In phase I, enzymes such as
cytochrome P450 oxidases introduce reactive
or polar groups into xenobiotics.
 Phase II: These modified compounds are then
conjugated to polar compounds in phase II
reactions. These reactions are catalyzed by
transferase enzymes such as glutathione S-
transferases.

7. Drug Metabolism: Phases
Fig: Phase I and II of the metabolism of a lipophilic
xenobiotics
 Phase III: Finally, in phase III, the conjugated
xenobiotics may be further processed, before being
recognized by efflux transporters and pumped out of
cells.

8. Drug Metabolism: Phases
Fig: Cytochrome P450 oxidases, which are important
enzymes in xenobiotics metabolism.

9. Drug Metabolism: Permeable
Barriers
 All organisms use cell membrane as hydrophobic
permeability barriers to control access to their
internal environment polar compounds cannot
diffuse across these cell membranes, and the
uptake of useful molecules is mediated through
transport proteins and substrate is selected
specifically from the extracellular fluid. As a result
hydrophilic molecules cannot enter the cell,
because they are not recognized by any specific
transporters. On the other hand, diffusion of
hydrophobic compounds across these barriers
cannot be controlled, and organisms, therefore,
cannot exclude lipid-soluble xenobiotics using
membrane barriers.

10. Drug Metabolism: Permeable
Barriers
 However, the existence of a permeability barrier
means that organisms were able to evolve
detoxification systems that exploit the
hydrophobicity common to membrane-permeable
xenobiotics. These systems therefore solve the
specificity problem by possessing such broad
substrate specificities that they metabolize almost
any non-polar compound. Useful metabolites are
excluded since they are polar, and in general
contain one or more charged groups.

11. Drug Metabolism: Factors That
Effect Drug Metabolism
The duration and intensity of pharmacological action
of most lipophilic drugs are determined by the rate
they are metabolized to inactive products. The
Cytochrome P450 monooxygenase system is the most
important pathway in this regard. 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 pro-drug
into a drug, enzyme induction can speed up this
conversion and increase drug levels, potentially
causing toxicity.

12. Drug Metabolism: Factors That
Effect Drug Metabolism
Various physiological and pathological factors can also
affect drug metabolism. Physiological factors that can
influence drug metabolism include –
 Age,
 Individual variations (e.g. pharmacogenetics),
 Enterohepatic circulation,
 Nutrition, etc.
In general, drugs are metabolized more slowly in
fetal, neonatal and elderly humans and animals than
in adults.

13. Prodrug: Definition
A prodrug is a medication that is administered in an
inactive or less than fully active form, and is then
converted to its active form through a normal
metabolic process, such as hydrolysis of an ester
form of the drug.
According to IUPAC: Compound that undergoes
biotransformation before exhibiting pharmacological
effects.

14. Prodrug: Importance
 A prodrug is a precursor chemical compound of a
drug.
 A prodrug is used instead of the drug to improve
absorption, distribution, metabolism, and excretion
(ADME).
 Prodrugs are important for improving
bioavailability ; when the drug itself is poorly
absorbed from GIT.
 Prodrugs are important for improving the
interaction of the drugs with the cells
 The using of prodrugs reduces unintended side
effects of a drug, which is important in treatment
like chemotherapy.

15. Prodrug: Classification
Based on how the body converts the prodrug into the
final active drug form, the prodrugs have been
classified into two major types. They are-
 Type I: Prodrugs are bioactivated intracellularly.
 Type II: prodrugs are bioactivated extracellularly,
especially in digestive fluids or in the body's
circulation system, particularly in the blood.

16. Prodrug: Classification (Type I &
Type II Examples)
 Type I:Examples of these are anti-viral nucleoside
analogs that must be phosphorylated and the lipid-
lowering statins.
 Type II: Examples of Type II prodrugs are salicin
and certain antibody-, gene- or virus-directed
enzyme prodrugs used in chemotherapy

17. Prodrug: Classification (Sub
classification)
Both major types can be further categorized into
subtypes, based on factors such as,
in case of type I-
Whether the intracellular bioactivation location is also
the site of therapeutic action.
In case of type II-
Whether or not bioactivation occurs in the
gastrointestinal fluids or in the circulation system
Therefore,
 Type I (A):prodrugs include many antimicrobial
and chemotherapy agents (e.g., 5-flurouracil).

18. Prodrug: Classification (Sub
classification)
 Type I (B):This type of prodrug agents rely on
metabolic enzymes, especially in hepatic cells, to
bioactivate the prodrugs intracellularly to active
drugs.
 Type II (A): This type of prodrugs are bioactivated
extracelluarly, either in the milieu of GI fluids.
 Type II (B): This type of prodrugs are bioactivated
within the systemic circulation and other
extracellular fluid compartments .
 Type II (C): This type of prodrugs are bioactivated
near therapeutic target tissues/cells.

19. Prodrug: Classification (Sub
classification)
All the prodrugs in type II subclasses rely on common
enzymes such as esterases and phosphatases or
target directed enzymes.

20. Prodrug: Undesirable Properties
 Physical properties:
 Poor aqueous layer
 Low lipophilicity
 Chemical instability
 Pharmacokinetic properties:
 Poor distribution across biological membranes
 Good substrate for first pass metabolism
 Rapid adsorption / excretion when long-term effect
desired.

21. Prodrug: Steps Of Prodrug
Design
 Identification of drug delivery problem
 Identification of desired physicochemical properties
 Selection of transport moiety which will
 Give prodrug desired transport properties
 Be readilly cleaved in the desired biologocal
compartment.

22. Prodrug: Example Of Some
Prodrug
Fig: Enalapril, which is bioactivated by esterase to active
enalaprilat.

23. Prodrug: Example Of Some
Prodrug
Fig: Valaciclovin, which is bioactivated by esterase to active
aciclovir.

24. Thank
you