prodrugs ii prepared by professor mohamed ahmed moustafa professor mohamed ahmed moustafa professor...

Prodrugs IIProdrugs II

Prepared ByPrepared By Professor Mohamed Ahmed MoustafaProfessor Mohamed Ahmed Moustafa

Professor of Medicinal ChemistryProfessor of Medicinal Chemistry

DRUG DRUG TARGETINGTARGETING

Site-specific drug delivery attempts to obtain very Site-specific drug delivery attempts to obtain very

precise and direct effects at the precise and direct effects at the ‘‘site of actionsite of action’’ withoutwithout

subjecting the rest of the body to significant levels of the subjecting the rest of the body to significant levels of the

active agent. active agent.

Prodrugs for Site Specificity

The targeting of drugs for a specific site in the body by conversion to

a prodrug is plausible when the physicochemical properties of

prodrug are optimal for the target site.

It should be kept in mind, however, that when the lipophilicity of a drug is

increased, it would improve passive transport of the drug nonspecifically to all

tissues.

Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site SpecificityTo increase the site specificity of certain drugs, the To increase the site specificity of certain drugs, the

following means of preparing prodrugs are used:following means of preparing prodrugs are used:

1.1. Increase or reduction in volumeIncrease or reduction in volume

2.2. Alteration of hydrophilicity or solubilityAlteration of hydrophilicity or solubility

3.3. Introduction or removal of cationic or anionic moietiesIntroduction or removal of cationic or anionic moieties

4.4. Change of pKaChange of pKa

5.5. Incorporation of hydrocarbon or other suitable stable Incorporation of hydrocarbon or other suitable stable or labile moieties, and carriers that transport the or labile moieties, and carriers that transport the compound to specific organs or tissues and make it to compound to specific organs or tissues and make it to accumulate selectively there, where it is bioactivated.accumulate selectively there, where it is bioactivated.

Prodrugs for GITProdrugs for GIT

A nice objective of using prodrugs is to restrict the drug A nice objective of using prodrugs is to restrict the drug

action to the upper part of the action to the upper part of the GIT GIT

If we want to target drugs against an infection of the If we want to target drugs against an infection of the GIT, then we want to prevent the drugs being GIT, then we want to prevent the drugs being absorbed into the blood supply. absorbed into the blood supply.

How??How??

Retardation of the drug absorption, as in case of Retardation of the drug absorption, as in case of

sulfathiazolesulfathiazole

How would you decrease the absorption of this How would you decrease the absorption of this

drug?drug?

This can easily be done by using a fully ionized This can easily be done by using a fully ionized molecule which is incapable of crossing cell molecule which is incapable of crossing cell membranes.membranes.

The incorporation of strongly The incorporation of strongly hydrophilic moietieshydrophilic moieties

to the sulfonamides prevents their transport to the to the sulfonamides prevents their transport to the

bloodstream.bloodstream.

They are incapable of crossing the gut wall and are They are incapable of crossing the gut wall and are therefore directed efficiently against the GI therefore directed efficiently against the GI infection.infection.

Prodrugs for (increased) Site SpecificityProdrugs for (increased) Site Specificity

used as intestinal antibacterial agent.used as intestinal antibacterial agent.

These prodrugs act almost exclusively inside the intestinal tract.

The succinyl or phthalyl group is good enough to decrease

lipophilicity of the compound.

The hydrophilic group makes the molecule poorly absorbed,

preventing its transportation to the circulation.

N

SNH

S

NO O

H

OOHO

Prodrugs for (increased) Site Prodrugs for (increased) Site SpecificitySpecificity

BitolterolBitolterol, , a prodrug of the a prodrug of the -blocker -blocker

colterolcolterol.. The toluate groups in both aromatic hydroxyls The toluate groups in both aromatic hydroxyls

prevent the methylation of one of the groups prevent the methylation of one of the groups

by the enzyme COMT, until these groups are by the enzyme COMT, until these groups are

removed by hydrolysis by the esterases removed by hydrolysis by the esterases

present in the tissues and in the blood.present in the tissues and in the blood.

Bitolterol accumulates selectively in the Bitolterol accumulates selectively in the lungslungs, ,

where it partially and immediately releases where it partially and immediately releases

colterol, which stimulate colterol, which stimulate -adrenergic -adrenergic

receptors and then adenylatic cyclase, with receptors and then adenylatic cyclase, with

the consequent relaxation of the bronchial the consequent relaxation of the bronchial

smooth muscles.smooth muscles.

NHC(CH3)3

OH

O

O

O

O

H3C

H3C

NHC(CH3)3

OH

HO

HO

COOH

CH3

p-Toluic Acid

2

Esterase

Bitolterol

Colterol

Blood-brain barrier (BBB)Blood-brain barrier (BBB) is one of important is one of important membrane often targeted for drug delivery. membrane often targeted for drug delivery.

It is unique lipid-like protective barrier that prevents It is unique lipid-like protective barrier that prevents hydrophilic compounds from entering the brain hydrophilic compounds from entering the brain unless they are actively transported.unless they are actively transported.

a The blood brain barrier contains active enzyme a The blood brain barrier contains active enzyme

systems to protect the CNS even further.systems to protect the CNS even further.

۩ Consequently, molecular size and lipophilicity are Consequently, molecular size and lipophilicity are

often necessary, not sufficient, criteria for gaining often necessary, not sufficient, criteria for gaining

entry into the brain.entry into the brain.


✵Bodor and co-workers have devised a Bodor and co-workers have devised a reversible redox reversible redox drug delivery system (RRDDS)drug delivery system (RRDDS) for getting drugs into the for getting drugs into the

CNS and then, once in, preventing their effluxCNS and then, once in, preventing their efflux..

The approach is based on the attachment of a hydrophilic The approach is based on the attachment of a hydrophilic drug to a lipophilic carrier (drug to a lipophilic carrier (a dihydropyridinea dihydropyridine) thereby ) thereby

making prodrug that actively transported into the brainmaking prodrug that actively transported into the brain..

N

H H

CH3

N

H H

CH3

Prodrug residueBlood-brain barrier

O

XR

O

XR


Once inside the brain, the lipophilic carrier Once inside the brain, the lipophilic carrier is converted enzymatically to a highly is converted enzymatically to a highly hydrophilic species (positively charged), hydrophilic species (positively charged), which is then enzymatically hydrolyzed which is then enzymatically hydrolyzed back to the drug and N-methylnicotinic back to the drug and N-methylnicotinic acid, which is eliminated from the brain. acid, which is eliminated from the brain.

♫ The The oxidationoxidation of the dihydropyridine to of the dihydropyridine to

the pyridinium ion (half-life generally 20-the pyridinium ion (half-life generally 20-

50 min) prevents the drug from escaping 50 min) prevents the drug from escaping

out of the brain because it becomes out of the brain because it becomes

charged.charged.

♫ This drives the equilibrium of the This drives the equilibrium of the

lipophilic precursor throughout all of the lipophilic precursor throughout all of the

tissues of the body to favor the brain.tissues of the body to favor the brain.

N

H H

CH3

N

CH3

Enzymatic oxidation

O

XR

X

OR


N

H H

CH3

N

H H

CH3

Prodrug residueBlood-brain barrier

N

CH3

Drug release

by a suitable process

HX R+

N

CH3

HOOC

Enzymatic oxidation

Drug

O

XR

O

XR

X

OR


♫The functional group on the drug should be an amino, The functional group on the drug should be an amino,

hydroxyl, or carboxyl group.hydroxyl, or carboxyl group.

♫When it is a carboxylic acid, the linkage is an When it is a carboxylic acid, the linkage is an

acyloxymethyl ester, which decomposes as in acyloxymethyl ester, which decomposes as in

pivampicillin.pivampicillin.


♫Any oxidation occurring outside of the brain produces a Any oxidation occurring outside of the brain produces a

hydrophilic species that can be rapidly eliminated from hydrophilic species that can be rapidly eliminated from

the body.the body.

♫The released oxidized carrier is relatively nontoxic and The released oxidized carrier is relatively nontoxic and

easily eliminated from the brain.easily eliminated from the brain.

♫Although this is a carrier-linked prodrug, it requires Although this is a carrier-linked prodrug, it requires

enzymatic oxidation to target the drug to the brain.enzymatic oxidation to target the drug to the brain.

♫The oxidation reaction is a bioprecursor reaction. The oxidation reaction is a bioprecursor reaction.


The brain delivery of The brain delivery of -lactam antibiotics-lactam antibiotics for the possible for the possible

treatment of bacterial meningitis.treatment of bacterial meningitis.

Since the Since the -lactam antibiotics are hydrophilic, they -lactam antibiotics are hydrophilic, they

enter the brain very slowly, but they are actively enter the brain very slowly, but they are actively

transported back into the blood.transported back into the blood.

Therefore, they are not as effective in the treatment of Therefore, they are not as effective in the treatment of

brain infections as elsewhere.brain infections as elsewhere.

Bodor and co-workers prepared a variety of penicillin Bodor and co-workers prepared a variety of penicillin

prodrugs attached to the dihydropyridine carrier prodrugs attached to the dihydropyridine carrier

through various linkers and showed that through various linkers and showed that -lactam -lactam

antibiotics could be delivered in high concentrations antibiotics could be delivered in high concentrations

into the brain. into the brain.

RRDDSRRDDS

N

O

HN

O

NH2

S

O OO

O

N


Increasing the brain concentration of the inhibitory neurotransmitter Increasing the brain concentration of the inhibitory neurotransmitter -aminobutyric acid-aminobutyric acid

(GABA) results in anticonvulsant activity.(GABA) results in anticonvulsant activity.

GABA is too polar to cross the blood-brain barrier, so it is not an effective GABA is too polar to cross the blood-brain barrier, so it is not an effective

anticonvulsant drug.anticonvulsant drug.

To increase the lipophilicity of GABA, a series of GABT and To increase the lipophilicity of GABA, a series of GABT and -aminobutyric Schiff bases -aminobutyric Schiff bases

were synthesized.were synthesized.

ProgabideProgabide emerged as an effective lipophilic analog of GABA that crosses the blood- emerged as an effective lipophilic analog of GABA that crosses the blood-

brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.brain barrier, releases GABA inside the brain, and shows anticonvulsant activity.

N

NH2

O

F

Cl

OH


3.3.The synthesis of a glyceryl lipid (R=linolenoyl) The synthesis of a glyceryl lipid (R=linolenoyl)

containing onecontaining one GABA molecule and one vigabatrin GABA molecule and one vigabatrin

molecule, a mechanism-based inactivator of GABA molecule, a mechanism-based inactivator of GABA

aminotransferase and anticonvulsant drug.aminotransferase and anticonvulsant drug.

This compound inactivates GABA aminotransferase This compound inactivates GABA aminotransferase in in

vitro vitro only if brain esterases are added to cleave the only if brain esterases are added to cleave the

vigabatrin from the glyceryl lipid.vigabatrin from the glyceryl lipid.

It also is 300 times more potent than vigabatrin, It also is 300 times more potent than vigabatrin, in in

vivovivo, presumably because of its increased ability to , presumably because of its increased ability to

enter the brain. enter the brain.


D.D.the application prodrugs to site-specific drug delivery the application prodrugs to site-specific drug delivery

-Glutamyl dopa-Glutamyl dopa is an example of a site-specific is an example of a site-specific

prodrug of levodopa (L-dopa).prodrug of levodopa (L-dopa).

L-dopa is precursor of the neurotransmitter dopamine, L-dopa is precursor of the neurotransmitter dopamine,

which plays an important role in the CNS and also which plays an important role in the CNS and also

exerts receptor-mediated vasodilation in the kidney.exerts receptor-mediated vasodilation in the kidney.

Prodrugs for (increased) Site Prodrugs for (increased) Site SpecificitySpecificity

Intraperitoneal injection of Intraperitoneal injection of -glutamyl -glutamyl

dopa into mice led to the selective dopa into mice led to the selective

generation of dopamine in the kidney generation of dopamine in the kidney

as a consequence of the sequential as a consequence of the sequential

actions of actions of -glutamyl transpeptidase-glutamyl transpeptidase

and and L-aromatic amino acid L-aromatic amino acid

decarboxylasedecarboxylase, two enzymes that are , two enzymes that are

highly concentrated in the kidney.highly concentrated in the kidney.

The concentration of dopamine in the The concentration of dopamine in the

kidney after kidney after --glutamyl dopa glutamyl dopa

administration was five times higher administration was five times higher

than that after administration of an than that after administration of an

equivalent dose of L-dopa.equivalent dose of L-dopa.

NH2

CH

CH2C

NH

O CH2

C

OH

O

OHO

HO

HO


► This does occur in a very selective This does occur in a very selective

manner, suggesting that some N-manner, suggesting that some N-

acyl-acyl--glutamylsulfamethoxazole -glutamylsulfamethoxazole

derivatives may be useful as derivatives may be useful as

specific renal antibacterial agents specific renal antibacterial agents

and and -glutamyllevodopa or -glutamyllevodopa or --

glutamyldopamine as specific renal glutamyldopamine as specific renal

vasodilators.vasodilators.

NH

S

NH

O O

N

O

O

R

R =

OH

O

R'HN

R' = Acetyl, Butyl

N- Acetyl-L--glutamyl-sulfamethoxazole

Acetylase

Acetate + L--glutamyl-sulfamethoxazole

H2O -glutamyl transpeptidase

Sulfamethoxazole + Glutamic acid


E.E.Design a prodrug that requires activation by an Design a prodrug that requires activation by an

enzyme found predominantly at the desired site of enzyme found predominantly at the desired site of

action.action.

For example, For example, tumor cellstumor cells contain a higher contain a higher

concentration of phosphatases and amidase than do concentration of phosphatases and amidase than do

normal cells.normal cells.

Consequently, a prodrug of a cytotoxic agent could be Consequently, a prodrug of a cytotoxic agent could be

directed to tumor cells if either of these enzymes were directed to tumor cells if either of these enzymes were

important to the prodrug activation process.important to the prodrug activation process.


Diethylstilbestrol diphosphate was originally designed Diethylstilbestrol diphosphate was originally designed

for site-specific delivery of diethylstilbestrol to prostatic for site-specific delivery of diethylstilbestrol to prostatic

carcinoma tissue.carcinoma tissue.

In general, though, this tumor-selective approach has In general, though, this tumor-selective approach has

not been very successful because the appropriate not been very successful because the appropriate

prodrugs are too polar to reach the enzyme site, the prodrugs are too polar to reach the enzyme site, the

relative enzymatic selectivity is insufficient, and the relative enzymatic selectivity is insufficient, and the

tumor cell perfusion rate is too poor. tumor cell perfusion rate is too poor.

designing prodrugs that are activated by enzymes found designing prodrugs that are activated by enzymes found mainly at the target sitemainly at the target site..This strategy has been used to design antitumour drugs This strategy has been used to design antitumour drugs because tumors contain higher proportions of because tumors contain higher proportions of phosphatasesphosphatases and and peptidasespeptidases than normal tissues. than normal tissues.For example, diethylstilboestrol diphosphate (Fosfestrol) For example, diethylstilboestrol diphosphate (Fosfestrol) has been used to deliver the oestrogen agonist has been used to deliver the oestrogen agonist diethylstilboestrol to prostatic carcinomas.diethylstilboestrol to prostatic carcinomas.

C C

C2H5

C2H5

O P OH

O

OH

OPHO

O

OH

Diethylstilboestrol diphosphate

C C

C2H5

C2H5

OHH2O

Diethylstilboestrol e


F.F.Certain glycosides of antiinflammatory steroids Certain glycosides of antiinflammatory steroids

designed to release the parent drugs in the colon.designed to release the parent drugs in the colon.

Since drug glycosides are bulkier and generally more Since drug glycosides are bulkier and generally more

hydrophilic than the corresponding drugs, their ability hydrophilic than the corresponding drugs, their ability

to cross the biological membranes is reduced.to cross the biological membranes is reduced.

Steroid glycosides are not cleaved by the enzymes of Steroid glycosides are not cleaved by the enzymes of

the small intestine.the small intestine.

In the colon, however, they are hydrolyzed by the In the colon, however, they are hydrolyzed by the

bacterial glycosidases, thus liberating the parent drugs bacterial glycosidases, thus liberating the parent drugs

in the large intestine. in the large intestine.


G.G.Two interesting examples are the prodrugs of N-Two interesting examples are the prodrugs of N-

acetylated sulfamethoxazole and of levodopa in which acetylated sulfamethoxazole and of levodopa in which

the carrier moieties are glutamic acid derivatives.the carrier moieties are glutamic acid derivatives.

►These prodrugs were designed on basis of the finding These prodrugs were designed on basis of the finding

of a particularly high concentration of an N-acylamino of a particularly high concentration of an N-acylamino

acid deacylase and acid deacylase and -glutamyl transpeptidase in the -glutamyl transpeptidase in the

kidneys and that these enzymes would hopefully kidneys and that these enzymes would hopefully

release the parent drugs in those organs.release the parent drugs in those organs.

Mutual OR Mutual OR Reciprocal prodrugsReciprocal prodrugs

Aspirin + ParacetamolAspirin + Paracetamol

The best aryl ester is The best aryl ester is

the the benorylatebenorylate, ,

which is a mutual which is a mutual

prodrug of Aspirin prodrug of Aspirin

and Paracetamol.and Paracetamol.

Advantages?Advantages?

O

O

O

O

O

NH

Sultamicillin (Self Protection)Sultamicillin (Self Protection)

N

S

O COOH

O O

Sulbactam(Beta-lactamase inhibitor)

N

S

O

HN

O

NH2

COOH

Ampicillin

N

S

O

C O

O

N

S

O

HN

O

NH2

C

O

O

O

O

Mutual Prodrug (Reciprocal Prodrugs)Mutual Prodrug (Reciprocal Prodrugs)

• Used for metastatic carcinoma of the prostate

• Promoiety also a drug!

• Prodrug is selectively taken up into estrogen receptor positive cells then urethane linkage is hydroylzed

• 17-alphaestradiol slow prostate cell growth

• Nornitrogen mustard is a weak alkylating agent

Actual alkylating species

CH3OH

HO

NHCl

Cl

NH+Cl-

ClNornitrogen mustard

Aziridine

Sodium phosphateandCarbon dioxide

CH3OPO3Na2

ON

OCl

Cl Estermustine Sodium PhosphateEmcyt® - Pharmacia & Upjohn

Famciclovir is a prodrug of penciclovir which is itself a Famciclovir is a prodrug of penciclovir which is itself a prodrugprodrug

Penciclovir is poorly absorbed from the gut owing to its Penciclovir is poorly absorbed from the gut owing to its polaritypolarity . .

Famciclovir is less polar and is absorbed more easily. It is Famciclovir is less polar and is absorbed more easily. It is then metabolized, mainly in the liver, to form penciclovir then metabolized, mainly in the liver, to form penciclovir

which is phosphorylated in virally infected cellswhich is phosphorylated in virally infected cells..

N

NN

NAcO

OAc

NH2 N

NN

NHO

OH

NH2

Liver

Famciclovir Penciclovir

N

NN

NO

OH

NH2

Viral thymidinekinase

PN

NN

NO

OH

NH2PPP Cell

kinase

FamciclovirFamciclovir

N

N

N

N

O

H2N

O

Famciclovir

O

O

N

N

N

N

HO

H2N

HO

N

N

N

N

O

O

H2N

H

HO

P

PP

N

N

N

N

HO

O

H2N

H

HO

Penciclovir

BioprecursorsBioprecursors

Bioprecursor ProdrugsBioprecursor Prodrugs Bioprecursor” prodrugBioprecursor” prodrug

A compound that is metabolized into an active drug, usually A compound that is metabolized into an active drug, usually by Phase I reactions; eg acetanilideby Phase I reactions; eg acetanilide

Do Do NOTNOT contain a carrier or promoiety contain a carrier or promoiety– Contain latent functionalityContain latent functionality

– Metabolically or chemically transformed into an active Metabolically or chemically transformed into an active drugdrug

– Types of activation at are predictableTypes of activation at are predictableOxidative (most common method)Oxidative (most common method)

ReductiveReductivePhosphorylation (antiviral agents)Phosphorylation (antiviral agents)

– Non-steroidal antiinflammatory

Use: Arthritis

Oxidation Example – Oxidation Example – Nabumetone – Nabumetone – RelafenRelafen®® – Smith Kline Beecham – Smith Kline Beecham

CH3

O

CH3O

OH

CH3OO

Series of oxidative

decarboxylation

Active form of the drugthat inhibits Prostaglandinbiosynthesis bycyclooxygenase

Reduction exampleReduction example - Mitomycin C - Mutamycin - Mitomycin C - Mutamycin®® - Bristol - Bristol Myers Myers Adenocarcinoma of the stomach and pancreasAdenocarcinoma of the stomach and pancreas

Bioprecursor ProdrugsBioprecursor Prodrugs

N

O

O

H2N

CH3

O

H2NO

NHOMe

H

A quinone -electron withdrawing

-H+

-CO2

-NH3

Electrophile

DNA

H2N

CH3NHN

OH

OH

N

H2N

CH3

O

H2NO

NH

H

+

H2N

CH3

O

H2NO

NHN

OH

OH

H+

-OCH3

N

OH

OH

H2N

CH3

O

H2NO

NHOMe

H

A hydroquinone -electron donating

Reduction

DNA

H2N

CH3NHN

OH

OH+

Further alkylation

Examples - BioprecursorExamples - Bioprecursor

Minoxidil is an antihypertensive that is also used as to prevent Minoxidil is an antihypertensive that is also used as to prevent hair loss (Rogaine/Regaine)hair loss (Rogaine/Regaine)

The active constituent is a Phase II metabolite, minoxidil sulfateThe active constituent is a Phase II metabolite, minoxidil sulfate

N

N NH2H2N

O

N

N NH2H2N

OSO3

minoxidil minoxidil sulfate

Phase IImetabolism

Pilocarpine BioprecursesPilocarpine Bioprecurses

N

NO

ORHO

N

NO

ORO

N

N

O

O

Invivo

R = Ethyl, Butyl, Benzyl, OR others

b) Sulfoxide Reductionb) Sulfoxide Reduction

The antiarthritis drug The antiarthritis drug sulindacsulindac is an indene isoster of is an indene isoster of indomethacin, which originally was designed as a serotonin indomethacin, which originally was designed as a serotonin analog.analog.

Sulindac is a prodrug for Sulindac is a prodrug for Sulindac sulfideSulindac sulfide, the metabolitc , the metabolitc reductive product reductive product

H

CH3

CH2COOH

R

F

R = S CH3 S CH3 S CH3

O

O

O

N-OxidationN-Oxidation

N-Oxidation prodrug activation reactionN-Oxidation prodrug activation reaction

is the reversible redox drug delivery is the reversible redox drug delivery

strategy for getting drugs into the brain.strategy for getting drugs into the brain.

In case of N-Methylpyridinium-2-In case of N-Methylpyridinium-2-

carbaldoxime chloride (2-PAM) is used as carbaldoxime chloride (2-PAM) is used as

an antidote to poisoning with an antidote to poisoning with

cholinesterase inhibitors.cholinesterase inhibitors.

Because of its charge and hydrophilicity Because of its charge and hydrophilicity

it does not penetrate the blood-brain it does not penetrate the blood-brain

barrier. barrier.

N

CH3

CH

NOH

2-PAM

.Cl

N

CH3

CH

NOH

2-PAM

.Cl

N

CH3

CH

NOH

Pro-2-PAM

Pro-2-PAM , the reduced

dihydropyridine form of 2-PAM,

readily enters she central

nervous system.

There it is oxidized to form 2-

PAM, which remains trapped in

the CNS since its charge reduces

its rate of transfer from the brain

back into the blood.

Pro-2-PAM

Phosphorylation examplePhosphorylation example– – Bioprecursor ProdrugsBioprecursor Prodrugs

O

HNO

O

I

OH

OP-OO

O-

Viral Thymidine

KinaseO

HNO

O

I

OH

HO

Iodoxuridine - Herplex®

Allergan - lipid soluble!Opthalmic product forHerpes simplex keratitisHigher affininty for viralkinases than mammaliankinases but some toxicity O

HNO

O

I

OH

OPOO

O-POP-OO

O-

O

O-

TWO mechanisms of action: 1. Inhibits DNA polymerase 2. Incorporatedinto DNA affording incorrect base pairing and template activity

ATP

Not lipid soluble

We have already seen 2 examples of this:We have already seen 2 examples of this:– Sulfasalazine – an azo compoundSulfasalazine – an azo compound– Methenamine – An urinary antibacterial agentMethenamine – An urinary antibacterial agent

RequirementsRequirements– Prodrug reach the site of action in high Prodrug reach the site of action in high

concentrationsconcentrations– Knowledge of high metabolism at siteKnowledge of high metabolism at site– Other factors Other factors

Extent of organ or site perfusionExtent of organ or site perfusion Information on the rate of prodrug conversion to the active form Information on the rate of prodrug conversion to the active form at both target and non-target sitesat both target and non-target sites Rate of input/output of prodrug from the target siteRate of input/output of prodrug from the target site

Limit side effects and increase effectivenessLimit side effects and increase effectiveness

Chemical Delivery SystemsChemical Delivery Systems

prodrugs ii prepared by professor mohamed ahmed moustafa professor mohamed ahmed moustafa professor...

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