metabolic changes of drugs & related organic cpd

Metabolic Changes of Drugs &

Related Organic Cpd.s

Metabolism plays a central role in elimina of drugs &

oer foreign copds.(xenobiotics) from

body.

A solid understanding of drug metabolic pathways is an

essential tool for pharmacists in eir selecting &

monitoring appropriate drug erapy for eir patients.

Most organic cpds. Entering body r- relatively lipid

soluble (lipophilic). To be absorbed ,ey must traverse

lipoprotein membranes of lumen walls of GIT. en

once in bloodstream,ese molecules can diffuse

passively through oer membranes & be distributed

effectively to reach various target organs to exert eir

pharmacological acs. Because of reabsorp in renal

tubules ,lipophilic cpds. r- not excreted to any substantial

extent in urine.

Xenobiotics en meet eir metabolic fate rough

various enzyme system at change parent cpds. To

render it more water soluble (hydrophilic).

Once metabolite is sufficiently water sol., it may be

excreted from body.ADME( absorp, distribu,

metabolism & elimina) principles is vital for successful

determination of drug regimens.

If lipophilic drugs, or xenobiotics,were not metabolized to

polar,readily excretable water-soluble products,ey

would remain indefinitely in body. Eliciting eir

biological effects.us, forma of water-soluble

metabolites not only enhances drug elimina, but also

leads to cpds. at r- generally pharmacologically inactive

& relatively nontoxic. consequently, drug metabolism

reacs have traditionally been regarded as detoxification

(or detoxification) processes.

Unfortunately ,it is incorrect to assume at drug

metabolism rx.s r- always detoxifying. Many

drugs r- biotransformed to pharmacologically

active metabolites. ese metabolites may have

significant activity at contributes substantially to

pharmacological or toxicological effect(s)

ascribed to parent drug. Occasionally, parent

cpd. is inactive wn administered & must be

metabolically converted to a biologically active

drug(metabolite). ese types of cpds. r- referred

to as prodrugs. In addition ,it is becoming

increasing clear at not all metabolites are

nontoxic.

Indeed, many adverse effects (e.g. tissue necrosis,

carcinogenicity, teratogenicity) of drugs &

environmental contaminants can be attributed

directly to forma of chemically reactive

metabolites at r- highly detrimental to body.is

concept is more important wn patient has a

disease state at inhibits or expedites xenobiotic

metabolism. Also , more & more drug metabolites r-

being found in our sewage systems. ese cpds.

may be nontoxic to humans but harmful to oer

animals or environment.

General pathways of drug metabolism:

Drug metabolism rx.s have been divided into 2

categories: phase 1 (functionalization) & phase II

(conjugation) rx.sPhase I (General pathways of drug metabolism)

Phase I (Functionalization Reacs):Introduces a polar funcal grp. e.g. OH, COOH,

NH2, SH, into drug molecule or xenobiotic

molecules to produce a more water soluble cpd.

is can achieved by :

a- direct introduc of funcnal grp. (e.g.

Aromatic & Aliphatic hydroxyla)

b- modifying (or unmasking) existing

functionalities (e.g. reduc of ketones &

aldehydes to alcohols, oxida of alcohols to

acids, hydrolysis of esters & amides to yield

COOH, OH , NH2 groups, reduc of azo & nitro

compounds to give NH2 moieties;oxidative N-,O-

& S-dealkyla to give NH2,OH & SH grps.) .

Although phase I Rx.s may not produce

sufficiently hydrophilic or inactive metabolites.

Generally provides a functional grp or

handle in the molecule in prepara for

phase II reacs.

Product may be polar enough to be

excreted.

Phase II (Conjuga Reacs):Attaches a small, polar& ionizable

endogenous compounds such as glucuronic

acid, sulfate, glycine and other amino acids to

the functional group"handle" of phase I

metabolites to produce water soluble

conjugated products. Conjugated metabolites

r- readily excreted in the urine & r- generally

devoid of pharmacological activity and toxicity

in humans.

* oer phase II pathways ,such as methyla

& acetyla, termina or attenuate biological

activity, whereas glutathione (GSH)

conjuga protects body against

chemically reactive cpds. or metabolites.

us phase I & phase II rx.s complement one

anoer in detoxifying & facilitating

elimina of ,drug & xenobiotics.

** Cpd.s w- existing funcal grps may go

directly to phase II.

** Drugs w- r- already hydrophilic r- largely

excreted unchanged.

Sites Of Drugs Biotransforma (metabolism)

- Biotransforma Rx.s may occur in many

tissues:

liver : most important organ in drug

metabolism & detoxifica of endogenous &

exogenous cpd.s (able to carryout, oxida,

reduc,hydrolysis)

divided into hepatic & extra hepatic:

1- Hepatic metabolism in liver (major site

of metabolism) for following reasons:

i- Rich in almost all drug-metabolizing enz.s

ii-A well-perfused organ i.e easy access to

metabolizing enz.s.

iii-Orally administered drugs w- r- absorb through GIT

must first all pass through liver before reaching

systemic circula us

extensively metabolised (first pass effect) extent of

metabolism may affect bioavailability ,in e.g. in

humanss,several drugs r- metabolized extensively by 1

st-pass effects.(Lidocain,isoproterenol,Meperidine,

Pentazocine,salicylamide & nitroglycerine)(decrease

oral bioavaliability) lidocaine r- removed so effectively

by 1 st-pass metabolism that they r ineffective wn given

orally,nitroglyceren buccally to bypass the liver)

2-Extra hepatic metabolism: overall

metabolism in tissues oer an liver.

i-Intestine:

* estrases & lipases r- abundant in intestinal

wall leading to hydrolysis of many ester

pro-drugs. (hydrolysis by esterase & lipase)

* Intestinal β-glucuronidase enzyme

hydrolyzes glucuronide conjugates ecreted in

bile, erefor librating free drug or its

metabolites for possible reabsorbed into

blood stream (enterohepatic circula or recycling) us drug stays longer in

body (affect dura of ac).

* Bacterial flora present in intestine & colon also

contribute to overall drug

metabolism. (w- include reduction of many Ar.azo & nitro

drugs to corresponding amine)

ii-Kidney, lungs, adrenal glands, placenta , brain etc..

(the full metabolic capabilities of the above organs have not

been fully explored.)

Role of Cyt.P-450 Monooxygenases(MO) in

Oxidative Biotransforma:

oxidative biotransforma processes r- most

common & important in drug metabolism.

general stoichiometry at describes oxida of

many xenobiotics (R-H) to eir corresponding

oxidazed metabollites (R-OH) is given by

following equa:

enzyme systems involved is called

mixed func oxidases(MFO) or

monooxygenases(MO). Rx requires

molecular oxygen + reducing agent NADPH

(reduced form of nicotinamide

adenosine dinucleotide phosphate) during

oxidative process.

b- NADPH- dependent cytochrome P-450 reductase.

c- NADH- linked cytochrome b5.

a + b + cofactors NADPH& NADH provide reducing

equivalents (electrons).

Cytochrome P450 is present in high

concentra in liver. Also present in oer

tissues e.g kidney

name cytochrome P-450 is due to reduced

(Fe2+) form enzyme – substrate complex

binding w- carbon monoxide giving a complex

w- UV-absorption maximum at 450 nm.

Types of oxida reacs catalyzed by Cytochrome P4501-Oxida of aromatic moieties (aromatic hydroxylation):

Oxida of aromatic cpds (arenes) by mixed

func oxidase enzymes to phenolic metabolites

(arenols) through epoxide intermediate (arene oxide).

Arene oxides intermediates r- extremely toxic, r-

highly electron deficient us react w- any

nucleophils in body.

Body rids itself by detoxification pathways.

Aromatic oxidation is a major pathway in

human.

most phenolic metabolites formed

from Ar. oxida undergo further

conversion to polar & water soluble

glucuronide or sulfate conjugates

w- r- readily excreted in urine.in

e.g. phenytoin,major urinary

metabolite of phenytoin found in

human is O-glucuronide conjugate

of p-hydroxyphenytoin

Rules for hydroxyla of substituents

aromatic rings:

* the substituents attached to the Ar.Ring

may influence the ease of hydroxyla.

1-hydroxylation rx.s proceed most readily in

activated (electron rich) rings.

2-deactivated Ar. Rings (w- containing e w-

drawing grp.s Cl, -N+R3,COOH,SO2NHR r-

generally slow or resistant to hydroxyla.

deactivating grp.s

present in antihypertensive

clonidine hydrochloride (Catapres)

may explain why this drug

undergoes little Ar.hydroxylation in

humans.

uricosuric agent Probencid

(Benemide) w- have e w-drawing

carboxy & sulfamido grp.s make it

resistant to undergo aromatic

hydroxyla.

In Ar. hydroxylation of Diazepam

(Valium) w- have 2 Ar. ring,the

hydroxylation in more activated ring.

A similar situation in anti-psychotic

agent: Chlorpromazine(Thorazine)&

in the p-hydroxylation of p-Chlorobiphenyl to p-chloro-p-

hydroxybiphenyl

Recent enviromental pollutants,

such as polychloronated biphenyl

system (PCBs) &

2.3.7.8,tetrachlorodibenzo-p-

dioxin(TCDD),

have attracted considerable public

concern oer eir toxicity & health

hazards bo resistant to Ar. oxidation,

b- of numerous electronegative

chlorine atoms in eir Ar. rings,

metabolic stability coupled to

lipophilicity of ese environmental

contaminants probably explains eir

long persistence in body once

absorbed.

* is rearrangement is a combined by

using D(deuteride )migra called NIH

shift. e.g: 4-deuterioanisole wn give its

metabolites……. Arene oxide ring

opens in direction that generates the

most resonance-stabilized

carbocation(+ve charge on C-3,C is

resonance stabilized by OCH3 .

direct loss of D+ may be more faverable

an NIH shift in some Ar.Oxid. rxs.

erefore,depending on substituent on

Arene,some Ar.hydroxyla rx.s do not

display any NIH shift.

Often,epoxide hydrase inhibitors,such

as cyclohexene oxide & 1,1,1-

trichloropropene-2,3-oxide,have been

used to demonstrate the detoxification

role of these enz. ,addition of inhibitors

is accompained frequently by increased

toxicity of these Arene oxide being

tested,b- formation of nontoxic

dihydrodiols is blocked

A few drugs (phenytoin, phenobarbital,

glutethimide)also yield dihydrodiol products as

a minor metabolites in humans.

A 2nd enzymatic rx.s involved nu. Ring

opening of Arene oxide by –SH grp p- in

GSH to yield the corresponding trans-1,2-

dihydro-1-S-glutathionyl-2-hydroxy

adduct,or GSH adduct.

•Wn administra of Bromobenzen to rats

causes sever liver necrosis.

- in vivo &in vitro studies indicate at

liver damage result from interac of

chemically reactive metabolite,4-

bromobenzene oxide.

PCAHs r- ubiquitous enviromental

contaminants at r- formed from auto

emission,refuse burning,industrial processes,

cigarette smoke & oer combustion processes.

oer carcinogenic PCAHs,7,12-dimethyl

benz[a]anthracene,also forms covalent

adduct w- NA(RNA), Arene oxide

intermediate binds covalently to guanosine

residues of RNA to yield 2 adduct.

Oxida of Olefins: metabolic oxida of olefinic ( -C=C-)

leads to form corresponding epoxide (or

oxirane) w- is more stable than Arene

oxide.(can measured in biological

fluids[plasma,urine])

e.g. of olefinic epoxida is metabolism

of anticonvulsant drug Carbamazepine

(Tegretol) in humans

Note:

biotransforma of olefinic cpds to epoxide

are minor product but furer conversion to

corresponding 1,2-diols, instance:

Anti-inflammatory agent Alcofenac

Epoxide intermediate is very toxic & is

highly e deficient will attack nu.s in

surrounding enz. leading to covalent

bonding to enzyme & its destruc

(suicidal complex),us causing inhibi of

enzyme & prolong dura.

** after administra of styrene in rats:

• toxicity of some olefinic cpd.s may result

from eir metabolic conversion to chemical

reactive epoxide,e.g. to clearly links

metabolic epoxida as a biotoxifica

pathway involves Aflatoxin B1

oer cpds such as vinyl chloride, stilbene

&carcinogenic estrogenic agent DES

undergo metabolic epoxida.

corresponding metabolites may be reactive

species responcible for cellular toxicity

seen w- is cpds.

Why? ese cpds causes inhibition of

oxidative drug metabolism? Explain

Oxida at Benzylic C atoms:

C attach to Ar. ring (benzylic posi)

r- susceptible to oxid. Forming

corresponding Alcohol(or carbinol)

•Oral hypoglycemic Tolbutamide

(Orinase)

Oer examples for benzylic grp.s

oxida in figure (4-8)

Oxida at Allylic C atoms:

microsomal hydroxyla at allylic C

atom e.g. psychoactive component

of marijuana , 1-THC

Anti-arrhythmic agent undergo allylic

oxida to give 3-OH quinidine, priciple

plasma metabolite found in humans,is

metabolite show significant antiarrhythmic

activity in animals & possibly in humans

Hexobarbital is a chiral barbiturate

derivative at exist in 2 enantiomeric

form.studies in humans indicate at

pharmacologically less active (R)(-)

enantiomer is metabolized more rapidly

an its (S)(+) isomer

H.W. Explain the bioactivation

pathway for hepatocarcinogenic

agent: Safrole

Oxida at C atoms to carbonyl & imines:MFO system also oxidizes C atom adjacent to carbonyl & imine(C=N) functionalities.

e.g. Benzodiazepines an important class of

drugs undergo oxidation to 3-hydroxyl

metabolite

Hydroxylation C atom to carbonyl

functionalities generally occurs only to

limited extent in drug metabolism .

e.g S/H drug glutethimide (Doriden) to

4-hydroxyglutethimide

Oxida at aliphatic & alicyclic C atoms:

alkyl or aliphatic C centers r- subject to

MFO.Oxida at terminal methyl grp.often

is referred to (ω oxida) & Oxida of

penultimate C atom (C next to last C) is

called (ω -1 oxida).

Aliphatic ω & ω -1 hydroxyla commonly

occur in drug w- straight or branched alkyl

chains. e.g. anticonvulsant valproic acid

(Depakene) (undergo bo ω & ω -1

Numerous barbiturates & oral

hypoglycemic Sulfonyl ureas also have

aliphatic side chains at r- susceptible to

oxida.

** S/H agent Amobarbital(Amytal)

undergoes extensive ω-1 oxida to

corresponding 3-hydroxylated

metabolite.

n-propyl side chain attached to oral

hypoglycemic agent Chlorpropamide

(Diabinese) undergoes extensive ω-1

hydroxyla to yield the 2 ry alcohol

2-hydroxy-Chlorpropamide as a

major urinary metabolite in humans.

Cyclohexyl grp.is commonly found in

many medicinal agents & also is susceptible

to MFO(Alicyclic hydroxyla)

*(wn monosubstituted cyclohexane ring)

hydroxyla occur at C-3 & C-4 lead to give

cis & trans conformational stereoisomers.

In humans, trans-4-hydroxycyclohexyl

prod. Is major metabolite,small amount of

other possible stereoisomers(cis-4,cis-3

&trans-3-hydroxycyclohexyl derivatives)

•Biotransforma of antihypertensive

Minoxidil(Loniten) yield 4-hydroxypiperidyl

metabolite.In dog, is prod. is major urinary

metabolite(29-47%),wheare in humans it is

detected in small amounts (3%).

Oxida involving C -Heteroatom systems:

** N,O functionalities r- commonly found in

most drugs & foreign cpds, S

functionalities

Two types of biotransforma reac:

1-Hydroxyla of the α-C atom attached

directly to heteroatom (N, O, S) giving an

unstable intermediate w- decomposes

leading to break of C-heteroatom bond

us causing Oxidative N-, O-, and S-dealkylation and oxidative deamination.

Must p- - H

2-Hydroxyla or oxida of heteroatom

(N, S only) → N-hydroxyla, N-oxide

forma, sulfoxida & sulphone forma.

* Several structural features

frequently determine w- pathway

will predominate,especially in C-N

system. metabolism of some N-

containing cpds is complicated by

C- or N-hydroxylated prod. may

undergo 2 ry rxs. to form oer,

more complex metabolic prod.

(oxime,nitrone,nitroso,imino)

N-containing cpds.can be devided

into 3 basic classes:

1-Aliphatic(1ry,2ry,3ry) & alicyclic

(2ry & 3ry) amines.

2-Ar. & heterocyclic N-cpds

3- Amides.

1- hepatic enzymes responsible for

carrying out -C hydroxyla rx.s r-

Cyt p 540 MFO.

2- hydroxyla or N-oxida rxs, appeare

to be catalysed not only by Cyt.p450 but

also by 2 nd class of hepatic MFO called

amine oxidase(N-oxidase),ese enzymes

r- NADPH-dependent flavoproteins &

don’t contain Cyt.p-450. ey require

NADPH & molecular O to carry out N-

oxida.

*** 3 ry Aliphatic & Alicyclic Amines:

- oxidative removal of alkyl grps

(particularly Me grps) from 3 ry aliphatic &

allicyclic amines is carried out by hepatic

cytochrom P-450 MFO enzymes.this rxs.--

--[oxidative N-dealkylation].

* Small alkyl grp. Me,Et.& Pro. r-

removed rapidly.

*N dealkyla of ter.butyl grp.is

not possible by carbinolamine

pathway b- -C hydroxyla can

not occur.

Many times, bisdealkylation of a 3 ry

amines leads to corresponding 1 ry

Aliphatic amine metabolite,w- is

susceptible to furer oxidation.e.g.

bisdemethyl metabolite of the H1-

histamine antagonist Brompheniramine

(Dimetane) undergoes oxidative

deamination & furer oxid.

*** Alicyclic 3 ry Amines undergo oxidative

N-dealkyla rx.s.

Direct N-dealkyla of t-butyl grp. through

carbinolamine intermediate not possible since

α-carbon hydroxyla cannot take place (no α H).

Can take place indirectly e.g. t-

butylnorchlorocyclizine is metabolized by the

removal of the t-butyl grp giving

norchlorcyclizine.

* Indirect N-dealkyla of t-butyl grps.is

not observed significantly. N-t-butyl

grp. P- in many β-adrenergic

antagonists,such as terbutaline &

salbutamol,remain intact & does not

appear to undergo any significant

metabolism.

Alicyclic 3 ry Amines often generate

lactam metabolite by -C hydroxyla

rx.s.

•Forma of lactam metabolites also has

been reported to occur to a minor extent.

N-oxida of 3 ry amines occurs w- several

drugs. true extent of N-oxide forma often is

complicated by susceptiblity of N-oxides to

undergo in vivo reduc back to parent 3 ry

amine.[e.g.H1-histamine antagonists

(orphenadrine, tripelenamine) ,phenothiazine

(chlorpromazine),tricyclic antidepressants

(imipramine) & narcotic analgesic

(morphine,codeine & meperidine) reported form

N-oxide products.in some instance ,N-oxides

possess pharmacological activity,e.g.

Imipramine N-oxide possesses antidepressant &

cardiovascular activity similar to at of parent

drug (Imipramine)

2ry & 1ry amine:

(parent drug or metabolites) r- susceptible

to oxidative N-dealkyla, oxidative deamina &

N-oxida rx.s

as in 3 ry amines, N-dealkylation of 2ry amines

proceeds by carbinolamine pathway.

dealkylation of 2ry amines gives rise to the

corresponding 1ry amine metabolite,e.g. -

adrenergic agent.

In general,dealkyla of 2ry amines

is belived to occur before oxidative

deamina. some evidence indicate

that may not always be true. direct

deamina of 2 ry amine also

occurred.

Some 2 ry alicyclic amines, like 3 amine

analogues,r- metabolized to eir

corresponding lactam derivative.

•Metabolic N-oxida of 2ry aliphatic &

alicyclic amines leads to several N-

oxygenated prod.

1 ry aliphatic amines(parent drug or

metabolites) r- biotransformed by oxidative

deamination (through carbinol amine),or by N-

oxidation.

In general,oxidative deamination of most

exogenous 1ry amines is carried out by the

MFO,Endogenous1ry amines (dopamine,

norepinephrine,tryptamine & serotonin) &

xenobiotics based on the structures of these

endogenous neurotransmiters r-

metabolized,via oxidative deamination by a

specialized family of enz.called MAOs.

* Structural feature ,especially the -

substituents of the 1 ry amine, often determine

whether C- or N-oxida will occur.e.g.

** xenobiotic,such as hallucination agents

** N-hydroxylation rx. Is not restricted to

-substituted 1ry amine such as

Phentermine.

Amphetamine has been observed to

undergo some N-hydroxyla in vitro to N-

hydroxyamphetamine….furer oxida to

oxime or conversion to imine

H.W. what major biotransforma

pathway can you expected for following

cpds.Explain by chemical rx?

Ar. Amine & heterocyclic N-cpds:

* biotransforma of Ar. Amines parallel

to the C-N oxida rxs. Seen w- aliphatic

amine.

** 3ry amine (Ar. Amine):

e.g. N-methyl aniline(2ry Ar. Amine)

1-N-dealkylation

2-N-hydroxylation

Note: 3 &2 ry Ar.amines r- encountered

rarely in medicinal agent, while 1 ry

Ar.amines r- found in many drugs & often

r- generated from enzymatic reduc of Ar.

Nitro cpds.,reductive cleavage of azo

cpds.& hydrolysis of Ar. Amide.

e.g. for azo amino dyes as N-methyl-4-amino

azo benzene (w- is carcinogenic agent),it is

very toxic b- it bind to DNA or RNA or prot. By

sulfate conjuga may lead to form a highly

reactive resonance stabilized nitrinium ion.

covalent adduct (.) this very reactive species &

DNA or RNA or prot.s have been observed.

Note: sulfate is not safe always

b- it a good leaving grp.

Note: methemoglobinemia toxicity is caused

by several Ar.amine ,including aniline &

dapsone,is a result of the bioactivation of the

Ar. Amine to its N-hydroxy

derivative.apparently ,N-hydroxylamine

oxidize the Fe(2+) from of hemoglobin to its

Fe(3+) form.this oxidized Fe(3+) state of

hemoglobin called (methemoglobin) or

ferrihemoglobin can no longer transport

O,w- lead to serious hypoxia or anemia.

Amides: ere str.formula is:

functonalities r- susceptible to oxidative C-N

bond cleavage by:

1- -C hydroxyla

2- N-hydroxyla rxs.

Note: Cyt.p-450 don’t act on the amide

linkage,amide linkage is effected only

by amidase enz.

•Path 1 is only for 2,3 amide if -C

hydroxyla occur.

If amide contain Ar.ring it causes toxicity

b- it can not enter path 1 but path 2 w- is

either form metabolites w- r- toxic or can

not be excreted.

Note: path 1-------safe

path 2------may be toxic if R is Ar.

**H.W. oxidation of anticancer agent

cyclophosphamide (cytoxan).

*** N-hydroxyla of Ar. ring (path 2) is

may be occur to minor extent, is of some

toxicological interest b- it leads to

chemical reactive intermediate forma,

e.g.hepatocarcinogenic 2-acetyl

aminofluorene (AAF) undergoes an N-

hydroxylation rx catalyzed by Cyt.p-450 to

form the corresponding N-hydroxy

metabolite(hydroxamic acid).

*** acetaminophene is a relatively safe

and non toxic analgesic agent if used at

therapeutic doses.

Acetaminophene(Paracetamol) can

enter phase II directly due to p- polar

grps. In its structure,so can conjugate

w- glucouronide acid & excreted. is

cpds.is highly conjugated due to p- of

large # of polar grp.s

Oxidation involving C-O systems:

1-oxidative O-dealkylation of C-O

systems(principally ethers) is catalyzed by

microsomal MFO.mechanistically,the

biotransformation involves an initial -C

hydroxylation to form either a hemiacetal or

a hemiketal,w- undergoes spontaneous C-O

bond cleavage to yield the dealkylated O-

species(phenol or alcohol) & a C moiety(ald.

Or ketone),small alkyl grp.s(methyl or ethyl)

attached to O r- O-dealkylated

rapidly.e.g.morphine is the metabolic

product of O-demethylation of codeine.

Oxidation involving C-S system:

C-S functional grp.s r- susceptible to

metabolic S-dealkyla,desulfura & S-

oxidation rx.

* 1 st 2 processes involve oxidative C-S

bond cleavage.

** S-dealkylation is analogous to O- & N-

dealkylation mechanistically.(involves -

C hydroxylation),can be seen in the

following cpd.s

In contrast to O- & N-dealkyla ,e.g. of

drugs undergoing S-dealkyla in

humans r- limited b- of the small # of S-

containing medicinals & competing

metabolic S-oxida processes.

** conversion C=S to C=O called

desulfuration .

E.g. for this biotransformation

thiopental to its corresponding oxygen

analogue pentobarbital.an analogus

desulfuration rx. Also occurs w- the

P=S moiety p- in a # of

organophosphate,such as parathion.

The mechanistic details of desulfuration r-

poorly understood,but it appears to involve

microsomal oxid.of the C=S or P=S double

bond.

** organosulfur xenobiotics commonly

undergo S-oxid. To yield sulfoxide

derivatives.several phenothiazine

derivatives r- metabolized by this

pathway.e.g. both S atoms p- in

thioridazine(Mellaril) r- susceptible to O-

oxidation.

*** S-oxid. Constitutes an important

pathway in the metabolism of the

H2-histamine antagonists

Cimetidine(Tagamet) & metiamide.

Sulfoxide drugs & metabolites may be

further oxidazed to sulfones(-SO2-

).e.g.immunosuppressive agent

oxisuran is metabolised to sulfone

moiety.

Oxidation of Alcohols & Aldeh.:

* many oxidative processes

(benzylic,allylic,alicyclic,or alliphatic

hydroxylation) generate alcohol or

carbinol metabolites as intermediate

products. If not conjugate,these

Alco.products r- further oxidized to :

1ry Alco.----oxid. Ald……….COOH

2ry Alco.-------oxid.------- Ketone

*** Ald. Metabolites resulting from:

a) oxida of 1 ry Alco.

b) oxidative deamina of 1 ry NH2.

*** Ald. often undergo facile oxida to

generate polar carboxylic acid derivatives.

Although 2 ry alco.s r- susceptible to oxida

,is rx. is not often important b- reverse

rx.,reduc of the ketone back to the 2ry

Alco.,occurs quite readily.in addi 2 ry Alco.

grp.,being polar & funcalized,is more likely

to be conjugated an ketone moiety.

*** several aldehyde

dehydrogenase,including aldehyde

oxidase & xanthine oxidase,carry out

the oxidation of aldehyde to the

corresponding acid.

*** metabolism of cyclic amines to

their lactam metabolites has been

observed for various drugs

e.g.(nicotine,phenmetrazine &

methylphenidate).it appeare that

soluble or microsomal dehydrogenase

& oxidases r- involved in oxidizing the

carbinol grp.of the intermediate

carbinolamine to a carbonyl moiety.

e.g. metabolism of medazepam

to diazepam,the intermediate

carbinolamine(2-

OHmedazepam) undergoes

oxidation of its 2-hydroxy grp.

To a carbonyl moiety.a

microsomal dehydrogenase

carries out this oxidation.

Other oxidative Biotransforma pathways:

*oxidative aromatiza or dehydrogena

* oxidative dehalogenation rx.s

Reductive Rx.s:

reductive processes play an important

role in metabolism of many cpds.

containing C=O,NO2 & N=N.

bioreduc of C=O generates alcohol

derivative.

NO2 & N=N reduc.s lead to amino

derivatives.

OH & NH2 moiety of metabolites r-

much more susceptible to conjugation

an funcal grp.s of parent cpds.

hence, reductive processes,facilitate drug

elimina.

Reductive pathways that r-

encountered less frequently in drug

metabolism include reduction of N---O

to their corresponding 3 ry amines &

reduction of sulfoxides to

sulfides.reductive cleavage of disulfide

linkages & reduction of C-C double

bonds also occur,but constitute only

minor pathways in drug metabolism.

1- Reduc of Alde. & ketone Carbonyls:

C=O moiety, particularly ketone grp.is

encountered frequently in many drugs. in addi ,

metabolites containing ketone & ald.

Functionalities often arise from oxidative

deamina of xenobiotics (propranolol,

chlorpheniramine,amphetamine) b- of eir ease

of oxida, ald.s r- metabolized mainly to

carboxylic acids. occasionally,aldehydes r-

reduced to 1 ry Alco.,ketone r- generally

resistant to oxida & r- reduced mainly to 2 ry

Alco. Alco.metabolites arising from reduc of

C=O cpds. generally undergo furer conjuga (

glucuronida).

w- required NADPH as a cofactor.

oxidoreductase enz.s that carry out both

oxida & reduc reac.s also can reduce

aldehyde & ketones. For e.g.,the

important liver alcoh. dehydrogenase is

NAD+-dependentoxidoreductase that

oxidize ethanol & other aliphatic alcohols

to aldehydes & ketone

* Aldehyde metabolites resulting from

oxidative deamination of drugs also

undergo reduction to a minor extent.for

e.g.,in humans the β-adrenergic

blocker propranolol is converted to an

intermediate aldehyde by N-

dealkylation & oxidative

deamination.although the aldehyde is

oxidized 1 ry to the corresponding

carboxylic acid(naphthoxylactic acid),a

small fraction also is reduced to the

alcohol derivative(propranolol glycol)

**Bioreduc of ketone often leads to

creation of an asymmetric center & ereby

,two possible sterioisomeric alcohol.e.g.

*** preferential forma of one

stereoisomer over oer is termed

product stereoselectivity in drug

metabolism.

** wn chiral ketones r- reduced,ey yield

2 possible diastereomeric or epimeric

alcohols.e.g.(R)(+) enantiomer of oral

anticoagulant warfarin

H.W. reduction of immunosuppressive

oxisuran

** reduc of β-unsaturated ketones

results in reduc not only of ketone

grp.s but of C=C. e.g. steroidal drugs

often fall into is class:

Reduc of Nitro & Azo cpds.:

Red. Of Ar.NO2 & N=N xenobiotics

leads to Ar.NH2 metabolites.

Azo red.,however,is belived to proceed

via a hydrazo intermediate (-NH-NH-)

that subsequently is cleaved

reductively to yield the corresponding

Ar.NH2.

** bioreduc of nitro cpds. is carried out

by NADPH-dependent microsomal &

soluble nitro reductases p- in the liver.

A multicomponent hepatic microsomal

reductase system requiring NADPH

appears to be responsible for Azo red.

In addi,bacterial reductases p- in the

intestine can reduce NO2 & N=N cpds.,

especially ose at r- absorbed poorly

or excreted mainly in bile.

•Some nitro xenobiotics, bioreduc

appears to be a minor metabolic pathway

in vivo,b- of competing oxidative &

conjugative rxs..under artificial anaerobic

in vitro incubation condis,however, ese

same nitro xenobiotics r- enzymatically

reduced rapidly.e.g.

Bacterial reductase p- in the intestine

also tends to complicate in vivo

interpretations of nitro reduc. e.g.[in

rats, antibiotic chloramphenicol is not

reduced in vivo by the liver but is

excreted in the bile &

subsequently,reduced by intestinal flora

to form the amino metabolite.

Enzymatic reduction of Azo cpds. e.g.

(other e.g. page 108)

Bacterial reductases p- in intestine play a

significant role in reducing azo xenobiotics.

particularly ose at r- abs. poorly. the 2

azo dyes tartrazine & amaranth have poor

oral abs. b- of the many polar & ionized

sulfonic acid grps.p- in their structures.these

2 dyes metabolized 1 ry by bacterial

reductases p- in the intestine.

Miscellaneous Reduc:

several minor reductive rx.s also occur :

1- reductive of N-oxides to 3 ry amine occur to

some extent.is reductive pathway is of interest

b- several 3 ry amines r- oxidized to form polar &

water soluble N-Oxide metabolites.

** if reduc of N-Oxide metabolites occurs to a

significant extent, drug elimina of parent 3

amine is impeded. N-Oxide reduc often is

assessed by administering pure synthetic N-

Oxide in vitro or in vivo & en attempting to

detect forma of the 3 ry amine.e.g.

•Reduction of sulfur & sulfoxide moieties, also

constitutes a minor reductive pathway.

Reductive cleavage of the disulfide bond in

disulfiram(Antabuse)yield N,N-

diethyldithiocarbamic acid(free or

glucuronidated) as a major metabolite in

humane.

Hydrolytic Rx.s:Hydrolysis of Esters & amides:

** the metabolism of ester & amide

linkages in many drugs is catalyzed by

hydrolytic enz.s p- in various tissues & in

plasma. metabolic product formed

(COOH,Alco-OH,Ar-OH& R-NH2)

generally r- polar & funcnally more

susceptible to conjugation & excre an

parent ester or amide drugs.

*** enz.s carrying out ester hydrolysis

include several nonspisific estrases found

in liver,kidney & intestine as well as

pseudocholinesterases p- in plasma.

Amide hydrolysis appears to be mediated

by liver microsomal amidases,esterase &

deacylases.

* hydrolysis is a major biotransforma

pathway for drug containing an ester

functionality.

** often,ester hydrolysis of the parent

drug leads to pharmacologically active

metabolites.e.g. antidiarrheal agent:

Diphenoxylate

* Many parent drugs have been chemically

modified or derivatized to generate so-called

prodrugs to overcome some undesirable

property (e.g. bitter taste,poor abs., poor

solubility, irrita at site of injec). rationale

behind the prodrug concept was to develop

an agent at,once inside the biological

system,would be biotransformed to the

active parent drug.

** improve poor oral absorption of

carbenicillin,lipophilic indanyl ester has

been formulated (Geocillin),once orally

abs.,the ester is hydrolyzed rapidly to the

parent drug.

•Amides r- hydrolyzed slowly in

comparison to esters.

Miscellaneous Hydrolytic rx.s:hydrolysis of recombinant peptide drugs &

hormones at N- or C- terminal amino acids

by carboxy-& aminopeptidases & proteases

in blood & other tissues is a well –

recogenized hydrolytic rx.e.g. of peptides or

protein hormones undergoing hydrolysis

include human insulin,growth

hormone(GH),prolactin,parathyroid

hormone(PTH) & atrial natriuretic factor

(ANF).

In addition to hydrolysis of amides &

esters,hydrolytic cleavage of other moieties

occur to minor extent in drug

metabolism,including the hydrolysis of

phosphate esters(diethylstilbestrol

diphosphate),sulfonylureas,cardiac

glycocides,carbamate esters &

organophosphate cpds.Glucuronide &

sulfate conjugates also can undergo

hydrolytic cleavage by β-glucuronidase &

sulfatase enz.s.hydration or hydrolytic

cleavage of epoxides & arene oxides by

epoxide hydrase is a hydrolytic rx.

8-Dealkylation of tertiary amines is faster than

secondary.

b- Oxidation of the nitrogen gives N-oxide which may

undergo reduction by reductase to give tertiary amine

again.

*N-oxide metabolite may possess

pharmacological activity. e.g. imipramine oxidized

to active N-oxide.

*N- oxidation is a minor metabolic pathway.

*Dealkylation more predominant.

II- Secondary aliphatic & alicyclic amines: 2 ry amine may be parent drug or metabolite

w- will undergo metabolism by

propranolol.....Crbinolamine..... 1ry.......ketoneβ-adrinergic

blocker ...........aliphatic amine … metabolite

ii-Oxidative deamination:

similar to N-dealkylation.

larger bulk of the molecule will be eliminated as

a carbonyl metabolit.

smaller bulk is removed as a small amine

moiety.

mechanism is again through α-C hydroxylagiving carbinolamine intermediate leading to C-

N cleavage & forma of carbonyl + amine.

In case of a drug like Norketamine (below)

α-C has no H thus no α-C hydroxylation is

possible thus deamination is not possible.

Bo reacs possible dealkyla first en

deamina is more favourable.

2 ry amines will undergo N-dealkyla before

deamina.

direct deamina of 2 ry amines takes place.

propranolol has two α- C atoms w- contain H

(both subject to hydroxyla) leading to two

possibilities :

A- N-Dealkyla followed by elimina of acetone

moiety giving 1 ry amine metabolite en

deamina giving carbonyl metabolite. OR

B-Direct dealkyla → elimina of

isopropylamine → aldehyde metabolit.

2 ry alicyclic amines undergo α hydroxylation

giving lactam metabolite e.g. phenmetrazine

(shown below).

ii-Oxidation of the nitrogen atom:Results in several oxygenated products.

· N-Hydroxylation will give the corresponding N-

hydroxylamine metabolites which will undergo

further oxidation (spontaneously or enzymatically) giving nitrone derivatives.

Example is N-benzylampheatmine shown

below).

III- 1 ry aliphatic amines:Parent drug or metabolite (Dealkyla of 1 ry

amine or bis dealkyla of 2ry amine) will

undergo:

a- Oxida of C- α to N- leading to oxidative

deamina (catalized by mixed function oxidases).Endogenous 1 ry amines e.g. dopamine, nor

epinephrine → oxidative deamina

(monoamine oxidases (MAO)) inactiva.

b- Oxida of N atom leading to forma of N-

hydroxyl amine (chemically unstable) w-

undergoes spontaneous or enzymatic oxida

giving nitroso & nitro derivatives.

Structural features of the α- substituent will

determine which oxidation will take place

that of the carbon or the nitrogen.

E.g. in phenteramine the Oxidation of

Nitrogen inevitableas shown below:

normally if α-C contains a H then either

oxidation of N to give N oxide or Oxidation

of C to give deamination as shown:

Dealkylation is a more common pathway than N-oxidation in human

IIII-Oxidation of aromatic amines and heterocyclic nitrogen compounds1-For tertiary aromatic amines: N-

dealkylation and N-oxidation e.g. N,N-

dimethylaniline.

2- 2ry aromatic amines:

3- 1 ry aromatic amines:

* more common in drug

*Can be formed from metabolism of other

compounds.

* Will be N-hydroxylated giving N-

hydroxylamine which is further oxidized to

the nitroso then nitro derivatives.

* Aromatic hydroxylamine.

* Nitrogen atoms in aromatic heterocyclic

moieties undergo N-oxidation (minor

extent)