prodrugs an approach to overcome problems related to ADME, for MPharm students sub- modern pharmaceutical and medicinal chemistry branch- quality assurance

2. Presenter : Ms. Jyotsna G. Patil
M.Pharmacy (Quality Assurance) 1st semester
Guided by: Mrs. Malathi Raghunath
GAHLOT INSTITUTE OF PHARMACY

3. What are
PRODRUGS
 The term ‘Prodrug’ describes compounds which
undergo biotransformation prior to exhibiting
their pharmacological effects.
 Prodrugs are pharmacologically inactive chemical derivatives of a drug
molecule that require a transformation (enzymatic or nonenzymatic)
within the body in order to release the active drug.
 Goal: improve ADME/Tox- or physicochemical properties
 Prodrug is successfully studied to target the drug specifically to site
of action for better therapy.

4. An illustration of the prodrug concept (Huttunen et al.,
2011)

5. Objectives of prodrug design
 Pharmaceutical objective
- improved solubility (chloramphenicol succinate ester)
- improved chemical stability (propranolol hemisuccinate ester)
- improved taste, odour (clindamycin palmitate)
- decreased irritation & pain (sulindac, clindamycin phosphate)
 pharmacokinetic objectives
- improved absorption (carbecillin, geocillin)
- decreased presystemic metabolism (acetonide of triamcinolone)
- improved absorption by non-oral routes (amino acid ester approach)
- improved prolong duration of action (fluphenazine ester prodrugs)
 pharmacodynamic objectives
- masking of reactive agent to improve its therapeutic index
- in situ activation of a cytotoxic agent (tirapazamine)

6. ADME
 ADME is an abbreviation in pharmacokinetics and
pharmacology for “ Absorption, Distribution,
Metabolism and Excretion.”
 It describes the disposition of pharmaceutical
compound within an organism.
 Absorption (bioavailability)
 Distribution (lower plasma concentration)
 Metabolism (metabolites- active/inactive)
 Excretion (termination of drug’s action)

7. Problems associated with ADME
 Incomplete absorption
 Too rapid or too slow transport of the drugs to the
body
 Incomplete systemic delivery of an agent
 Toxicity problems
 Poor site specificity

8. USE OF PRODRUGS TO OVERCOME
PHARMACOKINETIC BARRIERS
ABSORPTION PROBLEMS
Poor absorption due to:
1. High water solubility
2. Limited water solubility eg. cardiac glycoside such as
gitoxin.

9. Enhancement of Oral Absorption
Drug To improve absorption
Water soluble
vitamins
derivatization of thiolate ion to form lipid
soluble prodrugs
dopamine L-Dopa (active transport mechanism)
ampicillin acyloxymethyl ester (bacampicillin,
talampicillin and pivampicillin
carbenicillin α-carboxy ester (carbecillin, geocillin)
Gitoxin
(water insoluble)
penta acetyl prodrug

10. Prodrugs used in enhanced oral
absorption
ampicillin
8.44
O
N
NH2
NH
O
S
COO-
esterase
bacampicillin (R = CH3, R' = OEt)
pivampicillin (R = H, R' = t-Bu)
8.45
8.46
..
+ R'COOH
when
R' = OEt
EtOH
+ CO2
8.44
NH2
N
S
NH
O
Ph
O
O
O O
R
R'
O
NH2
N
S
NH
O
Ph
O
O
O
R
R H
O
OH
1)Ampicillin prodrugs

11. 2)Dopamine prodrug
 Dopamine is water soluble
 Levodopa is rapidly absorbed from the small intestine.

12. Enhancement of Ophthalmic
Absorption
 The usefulness of epinephrine as adrenergic agent in
the treatment of glaucoma is limited due to its highly
polar nature.
 Dipivalyl derivative of epinephrine formed by the
acylation of phenolic hydroxyl groups showed
enhanced therapeutic effectiveness.
 Lipid solubility of Dipivalyl derivatives is far superior
to its parent compound, which facilitates its transport
through a lipoidal barrier during corneal absorption.
 Dipivalyl Epinephrine: A New Pro-Drug in the
Treatment of Glaucoma

13. Enhancement of Percutaneous
Absorption
 Mefenide and corticosteroid
 The problem of poor percutaneous absorption of
corticosteroid was overcome by making various ester
prodrugs.
 Mefenide and corticosteroid are used in the treatment
of inflammatory, burn therapy, allergic and pruritic
conditions, but have limited application due to poor
percutaneous absorption.

15. Prevention of pre-systemic
metabolism
 Presystemic metabolism of drug is due to
- Phenolic moiety
- Oxidative N– and O– dealkylation
- Ester cleavage
- Peptide degradation
 Two types of drug
- rapidly degraded by the acid condition of the
stomach
- degrade due to enzymes present in the
gastrointestinal mucosa and liver

16. Prevention of pre-systemic
metabolism
 The first pass metabolism of a drug can be prevented if
the functional group susceptible to metabolism is
protected temporarily by derivatization.
 The prodrug approach was successfully used to
overcome the problem of considerable metabolism of
steroid drugs, propranolol, dopamine, morphine and
catecholamines

17. Prevention of pre-systemic
metabolism
DRUG PRODRUG APPROACH
Steroids Acetylated derivatives
Corticosteroids 17α, 21-acetonides
Propranolol Hemisuccinate ester
Dopamine L-Dopa
Morphine Diacetyl prodrug

18. Morphine prodrug
 Morphine is subject to extensive first-pass metabolism (a
large proportion is broken down in the liver), so, if taken
orally, only 40–50% of the dose reaches the central nervous
system.
 When someone takes heroin, either by means of injection,
smoking, the drug enters the bloodstream, then travels
towards the brain, hits the blood-brain barrier, already
having been converted to 6-mono-acetylmorphine
(6MAM) through hydrolysis. This compound, unlike pure
morphine, is lipid-soluble and races through into the brain
with almost no delay. Then the 6MAM rapidly breaks down
into morphine.

19. Morphine prodrug
Morphine Heroin

20. Corticosteroid prodrug
 Several corticosteroids undergo extensive first-pass
hepatic metabolism which can be prevented by use of
their ester or ether prodrugs.

22. Longer duration of action
 Prolongation of duration of action of a drug can be
accomplished by the prodrug approach and can take
two forms.
 First the input of drug in to the body can be controlled
by a prodrug/drug delivery formulation complex,
which by design releases drug at a controlled rate at
the absorption site, followed by conversion to drug
prior to or just after absorption.
 Second a prodrug can be designed wherein the
conversion to the parent drug becomes the release rate
limiting factor in the systemic milieu.

23.  This approach is most useful in case of neuroleptic
drugs to avoid large fluctuation in plasma levels.
 This could be successfully achieved by administering
heptanoate and decanoate esters of fluphenazine in
sterile sesame oil.
Fluphenazine prodrug
 Fluphenazine is a short acting piperazine
phenothiazine.
 Onset of action: within 1 hr.
 Duration of action: 6 to 8 hr.
 Reported half life: 13 to 33 hr. or more

24. Cont...
 Fluphenazine esters in sesame oil slows their release
resulting in longer duration of action.
 Onset of action: 24 to 72 hr.
 Avg. duration of action: 2 to 3 weeks.

25. To Diminish Local and Systemic
Toxicity of Drugs
 Therapeutic activity without toxicity
 Very difficult unless site specific delivery of drug is
achieved
 Various non steroidal anti inflammatory drugs like
salicylic acid and indomethacin severely damage the
GI mucosa due to presence of free carboxylic group.

26. Cont…
 Few other therapeutic agents such as sulindac sulfide,
5, 5-ethyl phenylhydrazine and phenytoin, and
antibiotic such as adriamycin suffer with the problem
of toxicity due to inadequate aqueous solubility,
improper distribution and high tissue distribution
respectively