Physicochemical Properties of Drugs (Ch 18)

These are physical, chemical and structural properties of

a molecule that are often able to be quantified
Include solubility, hydrophobicity, electronic effects of
substituents, ionisability, size (steric effects), shape
(stereochemistry)
Some of these properties are readily quantified and can
be used in Quantitative Structure-Activity Relationship
(QSAR) studies - see Peter Karusos lectures

No 1

Hydrophobicity

hydrophobicity of a drug determines how well it crosses

cell membranes and may be important for drug-receptor
interactions
hydrophobicity is also a factor in the absorption,
distribution and excretion of drug in body (see later for
more details)

No 2
 Hydrophobicity

Activity of a drug generally decreases as go to higher P

Why?

No 3

Hydrophobicity
anaesthetics and other drugs acting on the CNS should
have a logP ~2
Log P ~2 allows the drug to enter the blood brain barrier
conversely drugs which are designed to act elsewhere in
the body should have log P significantly differing from 2
(lower) N
MeO

R
e.g. N N
H

cardiotonic agents

(a) R = OCH3 log P = 2.59

O
(b) R = SCH3 log P = 1.17 sulmazole

No 4
 Electronic effects

electronic effects of substituents will affect drug

ionisation and polarity (especially important for drugs
that have acidic/basic groups)
drug ionisation and polarity in turn may affect how easily
a drug can pass through cell membranes and how
strongly it binds to the receptor site, as well as its
solubility and bioavailability at various sites of the body
(e.g. stomach, blood, gastrointestinal tract - different
pHs)

No 5

Solubility
generally, solubility is a function of the molecules size and
the relative proportion of hydrophilic and hydrophobic
groups
some generalisations:
ionic groups such as carboxylate and ammonium are
water solubilising
drugs that are salts of carboxylic acids (RCOO-Na+) and of
amines (RNH3+Cl-), are water soluble
free amine and carboxylic acid, ether, alcohol, ketone, and
nitrile groups are partially water solubilising
aliphatic, aromatic, and halogen groups increase lipid
solubility of drugs
No 6
 Solubility

e.g.
the solubility of sodium benzoate (Ph-CO2- Na+) is 56
g/100 mL; for benzoic acid (Ph-CO2H) its 0.34 g/100
mL, and for toluene (Ph-CH3) its 0.0067 g/100 mL
a drug is insoluble if its solubility is < 3.3% in water

No 7

Solubility
bioavailability - drugs require some appropriate balance of
water-lipid solubility
they need to be water soluble to dissolve in the gastrointestinal
tract (GIT) if taken orally & to dissolve in the bloodstream
BUT they need to be fat soluble to penetrate cell membranes,
which is generally necessary to reach their target site
However, generally very high water solubility hinders
absorption from the GIT and reabsorption from tubular urine in
the kidney and for high lipid solubility, drugs may become too
insoluble to be used orally or enter the bloodstream and may
have low bioavailability due to coagulation into fatty globules
and storage in fat cells

No 8
 Solubility
the chemist can alter the solubility of a parent drug when
desirable by making a suitable derivative of the drug
for example, chloramphenicol, which is fairly water insoluble,
can be converted to the water soluble sodium
chloramphenicol monosuccinate, which is suitable for
injection into veins (intravenous use)
hydrolysis of the salt (via esterase) in vivo gives
chloramphenicol, the active antibiotic
CHCl2
CHCl2
O O O -+
HN
HN O Na
O2N OH
O2N O
OH O
OH
chloramphenicol sodium chloramphenicol monosuccinate

No 9

Solubility
many drugs act as weak acids/bases - this affects
solubility and in turn absorption and excretion in the
body
a) carboxylic acids
R-CO2H + H2O R-CO2- + H3O+
for most carboxylic acid drugs, e.g. aspirin, ibuprofen
have pKa ~ 3-5
OAc Me
O
CO2H Me
OH
Me
aspirin ibuprofen
No 10
 Solubility

b) amines-ammonium ions
R-NH3+ + H2O R-NH2 + H3O+
typically, conjugate acids of amine drugs, e.g.
amphetamine have pKa ~ 8-10

NH2

Me
amphetamine

No 11

Solubility

c) Carbon acids, Sulfonamido acids and Imido acids

a few drugs are classified as carbon acids,
sulfonamido acids and imido acids
an example carbon acid is phenylbutazone, with pKa =
4.5. (Note that the pKa of methane as a carbon acid is
well over 30)
O
N
H
N
CH2CH2CH2CH3
O

phenylbutazone

No 12
 Solubility

example sulfonamido acids are sulfacetamide (pKa =

5.4), sulfisoxazole (pKa = 5) and sulfapyridine (pKa = 8.4)

O
O O
H2N S N CH3 H2N S N N
H H O
O O

sulfacetamide sulfisoxazole

O
H2N S N
H
O N

sulfapyridine

No 13

Solubility

examples of imido acids are phenobarbital (pKa = 7.5)

and the anticonvulsant phenytoin (pKa = 8.3)
Their acidities also can be rationalised on the basis of
the stability of their conjugate bases via electron
delocalisation

O O O
NH
HN NH HN
O
O phenytoin

phenobarbital

No 14
 Pharmacokinetics and Pharmacodynamics

The simplest definition of pharmacokinetics is: the

study of the movement of drugs within the body -
encompasses absorption, distribution, metabolism and
excretion (ADME) of the drug. i.e. WHAT THE BODY
DOES WITH THE DRUG

No 15

Pharmacokinetics and Pharmacodynamics

pharmacodynamics is: the study of the

pharmacological response to a drug, i.e. WHAT A DRUG
DOES TO ITS TARGET
- WHAT THE DRUG DOES WITH THE BODY IF IN VIVO
- G. Patrick notes pharmacodynamics is the study of how
molecules interact with targets such as receptors and
enzymes. May be carried out on pure target and isolated
cells or tissues (as well as in the body)

No 16
 Pharmacokinetics - fate of the drug in
the body (Ch 11)
consider taking a pill (oral drug)
drug must dissolve in aqueous system, survive the acid of
the stomach, then be absorbed from the GIT, via
membrane into bloodstream
drug must survive enzymes in the bloodstream and the liver
if the drug is anionic it may get bound by plasma/serum
protein (e.g. serum albumin)
if the drug is cationic it may be bound by nucleic acids
drug has to avoid excretion by the kidney/bile ducts
drug aimed at brain must cross blood-brain barrier
if enzymes are the target, drug may need to negotiate
further cell membranes
No 17

Pharmacokinetics - fate of the drug in the

body
GI TRACT BLOOD TISSUES

Stored Drug Stored Drug

Drug Free Drug Free Drug Drug-Receptor

Complex [Signal] Effect

Metabolites Metabolites Metabolites (Vertical dashed lines represent cell membranes)

Excreted Drug Excreted Drug

Excreted Metabolite Excreted Metabolite

No 18
 Pharmacokinetics - fate of the drug in the
body

the success of a drug, especially if orally administered,

depends principally on its physicochemical properties
the drug has to be chemically stable enough not to
break down in the acid conditions of the stomach
the drug has to be metabolically stable enough so that it
survives hydrolytic enzymes present in the digestive
system, liver and bloodstream
the drug has to have the correct balance of hydrophilic
and hydrophobic groups

No 19

Pharmacokinetics - transport and

absorption of drug
transport of drugs in the body is often dependent on their
ability to penetrate lipoidal membranes
generally passive diffusion
rate of loss of drug from site of absorption
= -dC/dt = kC for non-ionisable drug
where C = concentration of drug at site and k is rate
constant
for ionisable drug, rate = kCu = kfuC
where Cu = concentration of unionised drug at site and
fu = fraction unionised
Note only unionised drug can pass through membrane
No 20
 Pharmacokinetics - transport and
absorption of drug
Note the stomach has an acidity ~ pH 1-3
small intestine is more basic with a pH gradient of pH = 5 at
the pyloric end (near stomach), to high pH = 8 towards the
colon end
plasma pH ~7.4
thus acidic drugs (e.g. carboxylic acids) are more readily
absorbed in the stomach than basic drugs
amines are more readily absorbed in the intestine
acidic drugs are expected to be more readily absorbed in the
stomach than intestine from acidity considerations, but
primary source is the intestine. Why?
No 21

Pharmacokinetics - absorption of drug -

size and polarity

in general most useful drugs have a molecular weight

less than 500 - often because higher molecular weight
drugs have too many polar functional groups
Lipinskis rule of 5
poor absorption/cell permeation occurs when:
- there are more than 5-H bond donors
- the molecular weight is over 500
- the logP is over 5
- there are more than 10 H bond acceptors
No 22
 Pharmacokinetics - absorption of drug -
size and polarity

exceptions of Lipinskis rule of 5 include

compounds that are substrates for biological
transporters that can cross cell membranes by an active
process

No 23

Pharmacokinetics - drug excretion and

metabolism

drug metabolism is the in vivo chemical transformation of

a drug to another substance
generally, the products of drug metabolism are
biologically inactive, however, some drug metabolites are
as active, or more active, than the original drug
generally, drug metabolites are more polar, water-soluble
compounds than the original drug
generally, metabolism results in facilitated excretion of
drug

No 24
 Pharmacokinetics - drug excretion and
metabolism

drug metabolism is a detoxification mechanism

employed by the body to get rid of foreign substances
drug metabolites may be excreted in the bile or in urine
some drugs may be excreted intact
metabolism takes place mainly in the liver and to a
lesser extent, in other organs, e.g. lungs, kidney, brain,
intestine
two categories of metabolism: PHASE I and PHASE II
metabolism

No 25

Pharmacokinetics - drug excretion and

metabolism
Phase I metabolism generally involves oxidation, reduction,
or hydrolysis of drugs in vivo
e.g. Oxidation (usually catalysed by cytochrome P-450)
Oxidation of 'exposed' alkyl groups

R-CH3 RCH2OH R R OH

Me
e.g. Me O
O
CH2OH
Me
OH
OH Me
Me
ibuprofen

Me
O
CO2H
OH
Me

No 26
 Pharmacokinetics - drug excretion and
metabolism

Oxidation of alkenes and aromatic rings

R R R O R
R R OH
R R R R

OH
e.g.
O
O N
N
O
O
glutethemide

No 27

Pharmacokinetics - drug excretion and

metabolism

oxidative dealkylation
d) Oxidative dealkylation (of alkyl groups bonded to X; X = O, N, S)
OH OH
OH
H3C N H3C H3C N O
O N +
O
O H H

OCH3 OH
codeine OCH2OH morphine
codeine hemiacetal

O
+

N N H H
N

N CH3 N CH3 N CH3

imipramine imipramine
CH2OH H
CH3 desmethylimipramine (desipramine)
hemiaminal

No 28
 Pharmacokinetics - drug excretion and
metabolism
a) Ketoreductase/alcohol dehydrogenase
reduction
catalysed by
OH O OH OH
reductase H H CONH2
CONH2
enzymes that O O O N
O
generally employ warfarin N NADPH warfarin alcohol R
R
NADPH
O O OH
or NADH as O
SO2 SO2
N N
cofactors N
H
N
H
H H

acetohexamide acetohexamide alcohol

b) Azoreductase

H2N H2N
H2N N=N SO2NH2 H2N SO2NH2 +H2N NH2

prontosil sulfanilamide

No 29

Pharmacokinetics - drug excretion and

metabolism

O
c) sulfoxide reductase O
OH
OH

O S
S sulindac sulfide
sulindac

d) nitroreductase OH
OH
NHCOCHCl2
NHCOCHCl2 H2N
O2N OH
OH

chloramphenicol amine metabolite

No 30
 Pharmacokinetics - drug excretion and
metabolism

hydrolysis RCO2R -> RCO2H + ROH

RCONR2 -> RCO2H + HNR2
OH OH
OCH3 O O
O
N N
N H3C H3C
H3C
O O OH

O O
benzoyl ecgonine ecgonine
cocaine

H N
N OH
H2N H2N + N
O O H2N
procainamide paba

No 31

Pharmacokinetics - drug excretion and

metabolism

Phase II metabolism is coupling (conjugation) of a drug,

or its Phase I metabolite, with a polar, water-solubilising
biochemical to give a "conjugate
Phase I metabolism can provide a handle, i.e. a
nucleophilic group, for the Phase II conjugation reactions
The resulting conjugate has increased polarity and water
solubility, increasing its excretion rate in urine or bile
generally occurs in kidneys, gut wall and cell cytosol

No 32
 Pharmacokinetics - drug excretion and
metabolism

phenols, alcohols and amines form O- or N-glucoronides

by reaction with uridine diphosphate-glucoronic acid
(UDP-GA)
O
O

NH
NH
acetaminophen
COOH HO COOH
O O
O
OH O O O O
OH
OH O P O P O uridine HO P O P O uridine
OH
OH OH OH OH OH OH

UDP glucoronic acid acetaminophen glucoronide UDP

No 33

Pharmacokinetics - drug excretion and

metabolism

another example of a conjugate is a sulfate formed from a

drug, or its Phase I metabolite, and 3-phosphoadenosine-5'-
phosphosulfate (PAPS) by a process we could call
sulfation
NH2 NH2
N N
N N
O O O
N CO2H N
CO2H - N - N
O S O P O O P O O
O
O -O O
-O
OH O
O
O OH O S O O OH
salicylic acid P -O P
-O O-
O- O-
PAPS salicylic acid sulfate

No 34
 Pharmacokinetics - drug excretion and
metabolism

note that glucuronide and sulfate conjugates bear

negative charges at physiological pH, that is they are very
water-soluble anions, and predictably they are readily
excreted in the urine and poorly absorbed from the
gastrointestinal tract (and eliminated from it)
Other conjugates are known

No 35

Pharmacokinetics - drug excretion and

metabolism
Consequences of drug metabolism
metabolism generally leads to inactivation of drugs and is
therefore a detoxification mechanism
metabolism generally leads to more facile excretion of the
metabolised drug via the kidney and/or the gastrointestinal
tract (GIT). This is due to an increase in the polar nature of
the metabolite compared to the original drug
metabolism may lead to transformation of an inactive
compound to an active compound (drug)

No 36
 Pharmacokinetics - drug excretion and
metabolism

e.g. O Cl O Cl
O Phase 1 O
P N P N
oxidation
NH Cl NH Cl
aminal
O
H

O Cl O Cl
O elimination HO
spontaneous P N P N
NH2 Cl H
H NH2 Cl
O
O H
acrolein phospharamide mustard

No 37

Pharmacokinetics - drug excretion and

metabolism
Consequences of drug metabolism
a study of the activity of drug metabolites may lead to
replacement of the original drug with the metabolite, e.g. the
analgesic acetaminophen
metabolism may lead to toxic substances, e.g. metabolism of
the procarcinogen benzopyrene leads to benzopyrene 7,8-diol-
9,10-epoxide, which is a powerful alkylating agent and has been
shown to alkylate the guanine residues of DNA
O
N
N
O
N
10 H2O N NH
DNA
9 HO
HO HO
8 OH
O OH
7 HO
b enzo pyre ne 7,8 -ep oxide 7,8- dio l 7 ,8-diol- 9,10 -ep oxide OH guan ine-alt ered DNA

No 38
 Prodrugs (text 14.6)

Prodrugs = inactive compounds that can be

converted in the body by simple chemical/enzymatic
means to active drugs

No 39

Prodrugs

prodrugs use drug metabolism in a beneficial way

the prodrug typically must be converted to the active
drug once it has been absorbed into the blood
supply
the prodrug must also be designed so that any
groups cleaved from the molecule are non-toxic

No 40
 Prodrugs

Prodrugs are used to:

enhance membrane permeability
increase stability of drug (e.g. acid sensitivity,
metabolic stability)
increase duration of action
decrease drug cytotoxicity
increase site specificity

No 41

Prodrugs - enhancing membrane

permeability

for transport across membrane aqueous solubility

and lipophilicity are both important
if a drug is too polar it may not be able to cross
membranes
if a drug is too non-polar it may have low
bioavailability due to low aqueous solubility

No 42
 Prodrugs - enhancing membrane permeability
Drug with low lipophilicity
many drugs are either weak acids/bases/their salts
these drugs may dissociate/ionise BUT only unionised form can
cross membrane therefore ionisable drugs often have low
bioavailability
can use prodrugs to mask ionisable groups to aid membrane
crossing
may mask functional group important for receptor interaction, but
this will be regenerated

No 43

Prodrugs - enhancing membrane permeability

Drug with low lipophilicity

esterases and amidases are present in the blood
therefore ester and amide prodrugs can be used to mask
ionisable or polar groups and allow a drug to cross a fatty
cell membrane (e.g. between the GIT and the blood
supply)
the ester/amide group of the prodrug is then readily
hydrolysed in the blood to give the active drug

No 44
Prodrugs - enhancing membrane permeability

e.g. enalapril - ester prodrug of antihypertensive agent

enalaprilate

CH3
RO N
N
H
O O
CO2H

enalapril (R = CH2CH3); enalaprilate (R = H)

No 45

Prodrugs - enhancing membrane permeability

e.g. tranexamic acid (antifibrinolytic agent)

NH2CH2 CO2H

bioavailability (oral administration) ~35%

more lipophilic prodrug (ester prodrug):
O
H
NH2CH2 O C O OCH2CH3
CH3 O

absorbed >90% after oral administration

No 46
Prodrugs - enhancing membrane permeability

prodrug rapidly cleaved by enzyme hydrolysis

O
H
NH2CH2 O C O OCH2CH3
CH3 O

NH2CH2 CO2H

No 47

Prodrugs - enhancing membrane permeability

double ester types such as (acyloxy)alky esters shown below

are often used when the hydrolytic enzymes are susceptible to
steric effects and cant easily reach the simple aliphatic or
aromatic ester linkage and therefore the simple esters are not
sufficiently labile in vivo
the hydrolysis of the less sterically hindered terminal ester
bond produces a highly unstable -hydroxyalkyl ester, which
rapidly dissociates into the parent drug and an aldehyde
O
H
NH2CH2 O C O OCH2CH3
CH3 O

No 48
 Prodrugs - enhancing membrane permeability

e.g. Ampicillin antibiotic low oral bioavailability - why?

Pivampicillin virtually 100% oral bioavailability

H NH2 O H H
NH S

N
ampicillin O
CO2H

H NH2 O H H
NH S

N
pivampicillin O
CO2CH2OCOC(CH3)3

No 49

Prodrugs - increasing water solubility

several drugs show poor and variable absorption

(especially oral) due to insufficient aqueous solubility
some prodrugs are used to increase water solubility
OR
e.g. H H
Cl
N
Cl
O
OH
H
O2N

R = H chloramphenicol

R = CO(CH2)2CO2H chloroamphenicol succinate

No 50
 Prodrugs - increasing water solubility

prodrugs designed to increase water solubility often also

prove useful in preventing pain of some injections
caused by the poor solubility of drug at site of injection
e.g. the antibacterial agent clindamycin is painful when
injected, but using a phosphate ester prodrug improves
water solubility and prevents the pain
CH3
CH3CH2CH2 N H Cl
H
HH CH3
N
O
OH O
clindamycin phosphate H
OH SCH3
OPO2-
3

No 51

Prodrugs - for active transport

can design drugs to take advantage of carrier proteins in

cell membranes
e.g. amino acid transport - levodopa (prodrug for
dopamine)
HO CO2H HO

NH2 NH2
HO HO
levodopa dopamine - neurotransmitter

used in treatment of Parkinsons disease (condition due

in part to a deficiency of dopamine)

No 52
 Prodrugs - for active transport
dopamine cannot be used for treatment as it is too polar
to pass blood brain barrier
levodopa is even more polar BUT passes blood brain
barrier due to being actively transported by protein
carrier molecules that recognise amino acids

No 53

Prodrugs - for active transport

once levodopa is transported it is then decarboxylated to

dopamine

HO CO2H HO
decarboxylase
NH2 NH2
HO HO
dopamine - neurotransmitter

No 54
 Prodrugs - for active transport

many drugs purposely attached to amino acid to allow

active transport with amino acid recognising carrier
proteins
similarly nucleic acid bases are recognised by certain
protein carrier molecules and therefore some drugs are
now attached to nucleic acid bases for active transport
e.g. uracil mustard O
Cl

HN N

Cl
O N
H

No 55

Prodrugs - increasing drug stability in body

prodrugs may be used to decrease metabolism

drugs containing phenolic groups and amines are
particularly susceptible to metabolic processes leading to
deactivation and excretion
e.g. dopamine metabolised extensively by O-sulphation,
O-glucoronidation, O-methylation and deamination in
gastrointestinal wall and liver
prodrug below has all susceptible sites blocked
O
H3CH2CO O
HO
N CHCH2CH2SCH3
H3CH2CO O H NH2
O NHCOCH3 HO
O
dopamine

No 56
Prodrugs - increasing drug stability on shelf

e.g. prostaglandin E2 (PGE2), crystalline solid stable at

RT for short periods, but liquefies and decomposes after
a few months
due to: O
O
COOH
-H2O COOH
HO
PGE2 OH
PGA2 OH

O O
stop by using prodrug COOH

HO
OH

No 57

Prodrugs - increasing duration of action

prolonged duration of drugs obtained by:

sustained delivery of prodrug to systemic circulation
OR
slow conversion of prodrug to active parent drug

No 58
 Prodrugs - increasing duration of action

sustained delivery of prodrug to systemic circulation

extensively used with lipophilic drugs
e.g. neuroleptic fluphenazine (R=H)
S

N CF3

CH2CH2CH2 N N CH2CH2OR

after intramuscular injection in sesame oil ~6-8 hr

duration
ester R = COC9H19 ~3-4 weeks duration
No 59

Prodrugs - increasing duration of action

slow conversion of prodrug to active parent drug

e.g. 6-mercaptopurine SH

N N

N N
H
6-mercaptopurine

suppresses the bodys immune system response and is

therefore useful in protecting donor grafts BUT too
quickly eliminated from body Me N
N

S NO2 SH

N N N
N slow conversion
N N N N
H H
azathioprine 6-mercaptopurine

No 60
 Prodrugs - increasing duration of action

slow conversion of prodrug to active parent drug

can associate a very lipophilic group with an active drug
=> majority of drug gets stored in fat tissue
if lipophilic groups is slowly removed from active drug,
the drug is steadily released into the- blood stream
CO2
+ Cl
NH3
OH antimalarial agent
cycloguanil pamoate
N N CH2
+ Me -
CO2
H3N N Me
active drug OH
lipophilic anion

No 61

Prodrugs - increasing site specificity

drugs to be delivered to the brain can be coupled with

a quaternary carrier and reduced to neutral lipophilic
prodrug
CO2H CO2NHR CO2NHR
[H]
+ RNH2
N+ N+ N
CH3 CH3 CH3
N-methylnicotinic acid lipophilic prodrug

e.g. RNH2 NH2 HO NH2

HO
phenylethylamine dopamine

No 62
 Prodrugs - increasing site specificity

prodrug is distributed quickly throughout the body

including the brain, then enzymatically oxidised back to
quaternary salt, which is readily eliminated from the
body BUT not the brain

No 63
A/Prof Joanne Jamie, CBMS306/842

Prodrugs - increasing site specificity

not eliminated from the brain due to hydrophilic nature

preventing it from passing the blood brain barrier
therefore it is locked in the brain
the salt then undergoes slow enzymatic hydrolysis to
give active drug

CO2NHR CO2H
enzymatic hydrolysis
+ RNH2
N+ N+
CH3 drug
CH3

No 64
 Prodrugs - increasing site specificity

site specific bioactivation

via prodrug being activated at the desired site by
specific enzyme/property (e.g. pH) more present at site
than non-target tissues
e.g. kidney is highly active in uptake and metabolism of
-glutamyl derivatives of amino acids and amines
due to high concentration of -glutamyl transpeptidase
(enzyme capable of cleaving -glutamyl derivatives)
therefore possible to use -glutamyl derivatives of
active drug for site specificity at kidney
No 65

Prodrugs - increasing site specificity

site specific bioactivation

e.g. -glutamyl-levodopamine readily taken up in
kidney HO CO H HO 2
CO H 2

-glutamyl transpeptidase
NH NH2
HO HO
O
CH2
CH2
HC NH2
CO2H

HO NH2
decarboxylase

HO

dopamine

tissues other than kidney show low [free drug]

No 66
 Prodrugs - increasing site specificity

site specific bioactivation

e.g. cyclophosphamide - anticancer drug
converted into phosphoramide mustard via
phosphoramide enzyme
H
N O Cl H2N O Cl
P P
O N N
HO

Cl
cyclophosphamide phosporamide mustard Cl

high levels of phosphoramide enzyme present in some

tumour cells, i.e. specificity to tumour cells
also active drug highly toxic to all cells, prodrug not
No 67

Prodrugs - reduction of side effects

prodrugs can decrease side effects due to:

increased site specificity which can lead to decreased
toxicity and decreased side effects
prolongation of drug delivery may minimise toxicity due
to decreasing plasma peak concentrations

No 68
 Prodrugs - reduction of side effects

prodrugs can decrease localised toxicity/irritations

e.g. salicylic acid good painkiller but gastric bleeding due

to free -OH
O

H3C O O H
O O
esterases
OH
OH

aspirin - acetylsalicylic acid salicylic acid

prodrug

No 69