metabolic changes of drugs & related organic cpd
TRANSCRIPT
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)
