STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

UNI1 3 S1LkLCCnLMIS1k DkUG AC1ICN
ADVANCLD MLDICINAL CnLMIS1k
1CIC S1LkLCCnLMIS1k DkUG AC1ICN
IN1kCDUC1ICN
O 1he Creek word sLereos means solld" and sLereochemlsLry refers Lo chemlsLry ln Lhree
dlmenslons
O 1he foundaLlons of organlc sLereochemlsLry were lald by !acobus van'L Poff and !oseph Achllle
Le 8el ln 1874 lndependenLly of each oLher van'L Poff and Le 8el proposed LhaL Lhe four bonds
Lo carbon were dlrecLed Loward Lhe corners of a LeLrahedron
O ne consequence of a LeLrahedral arrangemenL of bonds Lo carbon ls LhaL Lwo compounds may
be dlfferenL because Lhe arrangemenL of Lhelr aLoms ln space ls dlfferenL
O lsomers LhaL have Lhe same consLlLuLlon buL dlffer ln Lhe spaLlal arrangemenL of Lhelr aLoms are
called sLereolsomers We have conslderable experlence wlLh cerLaln Lypes of sLereolsomers
Lhose lnvolvlng cls and Lrans subsLlLuLlon paLLerns ln alkenes and ln cycloalkanes
IMCk1ANCL CI S1LkLCCnLMIS1k IN DkUG AC1ICN
O 1he lmporLance of sLereochemlsLry ln drug acLlon ls galnlng greaLer aLLenLlon ln medlcal
pracLlce and a baslc knowledge of Lhe sub[ecL wlll be necessary for cllnlclans Lo make lnformed
declslons regardlng Lhe use of slngleenanLlomer drugs
O ,any of Lhe drugs currenLly used ln psychlaLrlc pracLlce are mlxLures of enanLlomers lor some
LherapeuLlcs slngleenanLlomer formulaLlons can provlde greaLer selecLlvlLles for Lhelr blologlcal
LargeLs lmproved LherapeuLlc lndlces and/or beLLer pharmacoklneLlcs Lhan a mlxLure of
enanLlomers
O 1he nomenclaLure for descrlblng sLereochemlsLry and enanLlomers emphaslzes Lhe poLenLlal
blologlcal and pharmacologlc dlfferences beLween Lhe 2 enanLlomers of a drug and hlghllghLs
Lhe cllnlcal experlence wlLh slngle enanLlomers of Lhe selecLlve seroLonln reupLake lnhlblLors
fluoxeLlne and clLalopram
O ln some cases boLh a mlxLure of enanLlomers and a slngleenanLlomer formulaLlon of a drug wlll
be avallable slmulLaneously ln Lhese cases famlllarlLy wlLh sLereochemlsLry and lLs
pharmacologlc lmpllcaLlons wlll ald Lhe pracLlclng physlclan Lo provlde opLlmal
pharmacoLherapy Lo hls or her paLlenLs
CnIkALI1 AND LNAN1ICMLkS
O hlrallLy ls formally deflned as Lhe geomeLrlc properLy of a rlgld ob[ecL (llke a molecule or drug)
of noL belng superlmposable wlLh lLs mlrror lmage
O ,olecules LhaL can be superlmposed on Lhelr mlrror lmages are achlral (noL chlral) hlrallLy ls a
properLy of maLLer found LhroughouL blologlcal sysLems from Lhe baslc bulldlng blocks of llfe
such as amlno aclds carbohydraLes and llplds Lo Lhe layouL of Lhe human body hlrallLy ls ofLen
lllusLraLed wlLh Lhe ldea of lefL and rlghLhandedness a lefL hand and rlghL hand are mlrror
lmages of each oLher buL are noL superlmposable 1
O 1he 2 mlrror lmages of a chlral molecule are Lermed enanLlomers Llke hands enanLlomers
come ln palrs 8oLh molecules of an enanLlomer palr have Lhe same chemlcal composlLlon and
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

can be drawn Lhe same way ln 2 dlmenslons (eg a drug sLrucLure on a package lnserL) buL ln
chlral envlronmenLs such as Lhe recepLors and enzymes ln Lhe body Lhey can behave dlfferenLly
O A racemaLe (ofLen called a racemlc mlxLure) ls a mlxLure of equal amounLs of boLh enanLlomers
of a chlral drug hlrallLy ln drugs mosL ofLen arlses from a carbon aLom aLLached Lo 4 dlfferenL
groups buL Lhere can be oLher sources of chlrallLy as well Slngle enanLlomers are someLlmes
referred Lo as slngle lsomers or sLereolsomers
O 1hese Lerms can also apply Lo achlral drugs and molecules and do noL lndlcaLe LhaL a slngle
enanLlomer ls presenL lor example molecules LhaL are lsomers of each oLher share Lhe same
sLolchlomeLrlc molecular formula buL may have very dlfferenL sLrucLures Powever many
dlscusslons of chlral drugs use Lhe Lerms enanLlomer slngle lsomer and/or slngle sLereolsomer
lnLerchangeably
O 1he 2 enanLlomers of a chlral drug are besL ldenLlfled on Lhe basls of Lhelr absoluLe
conflguraLlon or Lhelr opLlcal roLaLlon Lher deslgnaLlons such as u and L (noLe Lhe upper case)
are used for sugars and amlno aclds buL are speclflc Lo Lhese molecules and are noL generally
appllcable Lo oLher compounds
O 1he Lerms d or dexLro and l or levo are consldered obsoleLe and should be avolded lnsLead
Lhe 8/S sysLem for absoluLe conflguraLlon and Lhe +/- sysLem for opLlcal roLaLlon should be
used 1he absoluLe conflguraLlon aL a chlral cenLer ls deslgnaLed as 8 or S Lo unamblguously
descrlbe Lhe 3dlmenslonal sLrucLure of Lhe molecule 8 ls from Lhe LaLln recLus and means Lo
Lhe rlghL or clockwlse and S ls from Lhe LaLln slnlsLer for Lo Lhe lefL or counLerclockwlse 1here
are preclse rules based on aLomlc number and mass for deLermlnlng wheLher a parLlcular chlral
cenLer has an 8 or S conflguraLlon
O A chlral drug may have more Lhan one chlral cenLer and ln such cases lL ls necessary Lo asslgn an
absoluLe conflguraLlon Lo each chlral cenLer pLlcal roLaLlon ls ofLen used because lL ls easler Lo
deLermlne experlmenLally Lhan absoluLe conflguraLlon buL lL does noL provlde lnformaLlon
abouL Lhe absoluLe conflguraLlon of an enanLlomer lor a glven enanLlomer palr one
enanLlomer can be deslgnaLed (+) and Lhe oLher as (-) on Lhe basls of Lhe dlrecLlon Lhey roLaLe
polarlzed llghL pLlcal roLaLlons have also been descrlbed as dexLroroLaLory for (+) and
levoroLaLory for (-) 8acemaLes can be deslgnaLed as (8 S) or ()
DkUGS IN 8ICLCGICAL SS1LMS
O nanLlomers of a chlral drug have ldenLlcal physlcal and chemlcal properLles ln an achlral
envlronmenL ln a chlral envlronmenL one enanLlomer may dlsplay dlfferenL chemlcal and
pharmacologlc behavlor Lhan Lhe oLher enanLlomer
O 8ecause llvlng sysLems are Lhemselves chlral each of Lhe enanLlomers of a chlral drug can
behave very dlfferenLly ln vlvo ln oLher words Lhe 8enanLlomer of a drug wlll noL necessarlly
behave Lhe same way as Lhe SenanLlomer of Lhe same drug when Laken by a paLlenL lor a
glven chlral drug lL ls approprlaLe Lo conslder Lhe 2 enanLlomers as 2 separaLe drugs wlLh
dlfferenL properLles unless proven oLherwlse
O 1he dlfference beLween 2 enanLlomers of a drug ls lllusLraLed ln llgure 1 uslng a hypoLheLlcal
lnLeracLlon beLween a chlral drug and lLs chlral blndlng slLe ln Lhls case one enanLlomer ls
blologlcally acLlve whlle Lhe oLher enanLlomer ls noL 1he porLlons of Lhe drug labeled A 8 and
musL lnLeracL wlLh Lhe correspondlng reglons of Lhe blndlng slLe labeled a b and c for Lhe
drug Lo have lLs pharmacologlc effecL
O 1he acLlve enanLlomer of Lhe drug has a 3dlmenslonal sLrucLure LhaL can be allgned wlLh Lhe
blndlng slLe Lo allow A Lo lnLeracL wlLh a 8 Lo lnLeracL wlLh b and Lo lnLeracL wlLh c ln
conLrasL Lhe lnacLlve enanLlomer cannoL blnd ln Lhe same way no maLLer how lL ls roLaLed ln
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

space AlLhough Lhe lnacLlve enanLlomer possesses all of Lhe same groups A 8 and u as Lhe
acLlve enanLlomer Lhey cannoL all be slmulLaneously allgned wlLh Lhe correspondlng reglons of
Lhe blndlng slLe

O 1hls dlfference ln 3dlmenslonal sLrucLure prevenLs Lhe lnacLlve enanLlomer from havlng a
blologlcal effecL aL Lhls blndlng slLe ln some cases Lhe porLlon of a molecule conLalnlng Lhe
chlral cenLer(s) may be ln a reglon LhaL does noL play a role ln Lhe molecules ablllLy Lo lnLeracL
wlLh lLs LargeL ln Lhese lnsLances Lhe lndlvldual enanLlomers may dlsplay very slmllar or even
equlvalenL pharmacology aL Lhelr LargeL slLe ven ln Lhese cases Lhe enanLlomers may dlffer ln
Lhelr meLabollc proflles as well as Lhelr afflnlLles for oLher recepLors LransporLers or enzymes
IMCk1ANCL CI CnIkALI1 IN DkUGS
O ApproxlmaLely 30 of markeLed drugs are chlral and of Lhese approxlmaLely 30 are mlxLures
of enanLlomers raLher Lhan slngle enanLlomers
O ln Lhls secLlon Lhe poLenLlal advanLages of uslng slngle enanLlomers of chlral drugs are
dlscussed and some speclflc examples of slngleenanLlomer drugs currenLly on Lhe markeL are
glven
O SlngleenanLlomer drugs wlll become lncreaslngly more avallable Lo Lhe pracLlclng physlclan and
boLh Lhe slngleenanLlomer form and Lhe mlxLure of enanLlomers of a glven drug may be
avallable aL Lhe same Llme ln Lhese cases lL ls crlLlcal Lo dlsLlngulsh Lhe slngle enanLlomer from
Lhe racemlc form because Lhey may dlffer ln Lhelr dosages efflcacles slde effecL proflles or
even lndlcaLed use
O lL ls also lmporLanL Lo reallze LhaL Lhe safeLy and efflcacy daLa for a drug evaluaLed as a mlxLure
of enanLlomers are sLlll valld 1he lnLroducLlon of a slngleenanLlomer preparaLlon of a drug
prevlously approved as a mlxLure of enanLlomers does noL necesslLaLe LhaL Lhe slngle
enanLlomer should become Lhe sLandard of care 1he declslon Lo use a slngle enanLlomer versus
a mlxLure of enanLlomers of a parLlcular drug should be made on Lhe basls of Lhe daLa from
cllnlcal Lrlals and cllnlcal experlence
O 1he enanLlomers of a chlral drug may dlffer slgnlflcanLly ln Lhelr bloavallablllLy raLe of
meLabollsm meLabollLes excreLlon poLency and selecLlvlLy for recepLors LransporLers and/or
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

enzymes and LoxlclLy 1he use of slngleenanLlomer drugs can poLenLlally lead Lo slmpler and
more selecLlve pharmacologlc proflles lmproved LherapeuLlc lndlces slmpler pharmacoklneLlcs
due Lo dlfferenL raLes of meLabollsm of Lhe dlfferenL enanLlomers and decreased drug
lnLeracLlons
O lor example one enanLlomer may be responslble for Lhe LherapeuLlc effecLs of a drug whereas
Lhe oLher enanLlomer ls lnacLlve and/or conLrlbuLes Lo undeslrable effecLs ln such a case use of
Lhe slngle enanLlomer would provlde a superlor medlcaLlon and may be preferred over Lhe
racemlc form of Lhe drug
O SlngleenanLlomer formulaLlons of (S)albuLerol a 2adrenerglc recepLor agonlsL for LreaLmenL
of asLhma and (S)omeprazole a proLon pump lnhlblLor for LreaLmenL of gasLroesophageal
reflux have been shown Lo be superlor Lo Lhelr racemlc formulaLlons ln cllnlcal Lrlals ln oLher
cases however boLh enanLlomers of a chlral drug may conLrlbuLe Lo Lhe LherapeuLlc effecLs
and Lhe use of a slngle enanLlomer may be less effecLlve or even less safe Lhan Lhe racemlc
form
O lor example Lhe (-)enanLlomer of soLalol has boLh blocker and anLlarrhyLhmlc acLlvlLy
whereas Lhe (+)enanLlomer has anLlarrhyLhmlc properLles buL lacks adrenerglc anLagonlsm ln
addlLlon Lhe 8enanLlomer of fluoxeLlne aL lLs hlghesL admlnlsLered dose led Lo sLaLlsLlcally
slgnlflcanL prolongaLlon of cardlac repolarlzaLlon ln phase ll sLudles Lhe sLudles were
subsequenLly sLopped
O urrenLly Lhere ls no regulaLory mandaLe ln Lhe unlLed SLaLes or urope Lo develop new drugs
excluslvely as slngle enanLlomers 1he uS lood and urug AdmlnlsLraLlon (luA) pollcy regardlng
slngle enanLlomers was publlshed ln 1992 1hls sLaLemenL ls avallable aL Lhe luA Web slLe aL
wwwfdagov/cder/guldance/sLereohLm
O 1he luA leaves Lhe declslon Lo pursue a racemlc or a slngleenanLlomer formulaLlon of a new
drug Lo lLs developers buL Lhe cholce of a racemlc versus a slngleenanLlomer formulaLlon musL
be [usLlfled AlLhough boLh racemlc and slngleenanLlomer drugs wlll conLlnue Lo be developed
a hlgher proporLlon of slngle enanLlomers are belng submlLLed for new drug approval
O AlLhough many psychoLroplc drugs are elLher achlral (eg fluvoxamlne nefazodone) or are
already markeLed as slngle enanLlomers (eg serLrallne paroxeLlne esclLalopram) a number of
anLldepressanLs are currenLly markeLed as racemaLes lncludlng buproplon clLalopram
fluoxeLlne Lranylcypromlne Lrlmlpramlne and venlafaxlne
O Lher drugs ofLen used ln psychlaLrlc pracLlce lncludlng zoplclone meLhylphenldaLe and some
phenoLhlazlnes are also avallable as racemaLes f Lhese slngleenanLlomer formulaLlons are
belng developed for buproplon and zoplclone uexmeLhylphenldaLe (meLhylphenldaLe) has
also been lnLroduced recenLly
O ln Lhe case of clLalopram Lhe enanLlomer ls prlmarlly responslble for anLagonlsm of seroLonln
reupLake whlle Lhe enanLlomer ls 30fold less poLenL
O ln cllnlcal Lrlals boLh racemlc ()clLalopram (markeLed as elexa) and ()clLalopram
(markeLed as Lexapro) were slgnlflcanLly beLLer Lhan placebo for lmprovlng depresslon 1he
early daLa suggesL LhaL ()clLalopram has greaLer efflcacy Lhan ()clLalopram aL doses
predlcLed Lo be equlvalenL as well as equal efflcacy Lo ()clLalopram aL a dose LhaL produces
fewer slde effecLs
O verall ()clLalopram appears Lo have advanLages over racemlc clLalopram and ls a good
example of Lhe poLenLlal beneflLs of slngleenanLlomer drugs Powever Lhere ls currenLly no
evldence LhaL paLlenLs wlLh ma[or depresslon who are respondlng well Lo Lherapy wlLh
clLalopram beneflL from swlLchlng Lo clLalopram
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

O ln conLrasL Lhe aLLempL Lo develop a slngleenanLlomer formulaLlon of fluoxeLlne for Lhe
LreaLmenL of depresslon was unsuccessful Whlle ()fluoxeLlne and ()fluoxeLlne are slmllarly
effecLlve aL blocklng seroLonln reupLake Lhey are meLabollzed dlfferenLly
O 1he use of Lhe enanLlomer was expecLed Lo resulL ln less varlable plasma levels of fluoxeLlne
and lLs acLlve meLabollLes Lhan observed wlLh racemlc fluoxeLlne AddlLlonally ()fluoxeLlne
and lLs meLabollLes lnhlblL 92u6 a cyLochrome 9430 sysLem enzyme Lo a lesser exLenL Lhan
()fluoxeLlne and lLs meLabollLes
O As menLloned ln phase ll sLudles of ()fluoxeLlne Lhe hlghesL dose led Lo sLaLlsLlcally
slgnlflcanL prolongaLlon of cardlac repolarlzaLlon and Lhe sLudles were sLopped
O AlLhough racemlc fluoxeLlne has been shown Lo be a safe and effecLlve anLldepressanL for over
13 years Lhe ()enanLlomer formulaLlon was noL vlable due Lo safeLy concerns 1he experlence
wlLh ()clLalopram and ()fluoxeLlne hlghllghL Lhe poLenLlal dlfferences beLween enanLlomers
of a glven chlral drug and Lhe need Lo conslder slngleenanLlomer formulaLlons of a prevlously
racemlc drug on a casebycase basls
LNAN1ICSLLLC1IVI1 IN DkUG ADML
O ln chemlsLry an enanLlomer ls one of Lwo sLereolsomers LhaL are mlrror lmages of each oLher
LhaL are nonsuperposable (noL ldenLlcal) much as ones lefL and rlghL hands are Lhe same
buL opposlLe
O nanLlopure compounds refer Lo samples havlng wlLhln Lhe llmlLs of deLecLlon molecules of
only one chlrallLy
O nanLlomers have when presenL ln a symmeLrlc envlronmenL ldenLlcal chemlcal and physlcal
properLles excepL for Lhelr ablllLy Lo roLaLe planepolarlzed llghL (+/-) by equal amounLs buL ln
opposlLe dlrecLlons (alLhough Lhe polarlzed llghL can be consldered an asymmeLrlc medlum) A
mlxLure of equal parLs of an opLlcally acLlve lsomer and lLs enanLlomer ls Lermed racemlc and
has zero neL roLaLlon of planepolarlzed llghL
O nanLlomers of each oLher ofLen show dlfferenL chemlcal reacLlons wlLh oLher subsLances LhaL
are also enanLlomers Slnce many molecules ln Lhe body of llvlng belngs are enanLlomers
Lhemselves Lhere ls ofLen a marked dlfference ln Lhe effecLs of Lwo enanLlomers on llvlng
belngs ln drugs for example Lhe worklng subsLance ls ofLen one of Lwo enanLlomers whlle Lhe
oLher one ls responslble for adverse effecLs

nanLlomers of clLalopram 1he Lop ls ()clLalopram and Lhe boLLom ls ()clLalopram
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

O An example of such an enanLlomer ls Lhe sedaLlve Lhalldomlde lL was sold ln a number of
counLrles across Lhe world from 1937 unLll 1961 when lL was wlLhdrawn from Lhe markeL afLer
belng found Lo be a cause of blrLh defecLs
O ln Lhe herblclde mecoprop Lhe carboxyl group and Lhe hydrogen aLom on Lhe cenLral aLom
are exchanged (wlLh Lhe screen as plane of symmeLry) AfLer roLaLlng one of Lhe lsomers 180
degrees (ln Lhe same plane) Lhe Lwo are sLlll mlrror lmages of each oLher 1he mlrror lmage of
each enanLlomer ls superposable on Lhe oLher enanLlomer
O AnoLher example ls Lhe anLldepressanL drugs esclLalopram and clLalopram lLalopram ls a
racemaLe 11 mlxLure of ()clLalopram and ()clLalopram esclLalopram ()clLalopram ls a
pure enanLlomer 1he dosages for esclLalopram are Lyplcally 1/2 of Lhose for clLalopram
LNAN1ICSLLLC1IVL kLAkA1ICNS
O 1here are Lwo maln sLraLegles for Lhe preparaLlon of enanLlopure compounds 1he flrsL ls known
as chlral resoluLlon 1hls meLhod lnvolves preparlng Lhe compound ln racemlc form and
separaLlng lL lnLo lLs lsomers ln hls ploneerlng work Louls 9asLeur was able Lo lsolaLe Lhe
lsomers of LarLarlc acld because Lhey crysLalllze from soluLlon as crysLals each wlLh a dlfferenL
symmeLry A less common meLhod ls by enanLlomer selfdlsproporLlonaLlon
O 1he second sLraLegy ls asymmeLrlc synLhesls Lhe use of varlous Lechnlques Lo prepare Lhe
deslred compound ln hlgh enanLlomerlc excess 1echnlques encompassed lnclude Lhe use of
chlral sLarLlng maLerlals (chlral pool synLhesls) Lhe use of chlral auxlllarles and chlral caLalysLs
and Lhe appllcaLlon of asymmeLrlc lnducLlon 1he use of enzymes (blocaLalysls) may also
produce Lhe deslred compound
O nanLloconvergenL synLhesls ls Lhe synLhesls of one enanLlomer from a racemlc precursor
molecule uLlllzlng boLh enanLlomers 1hus Lhe Lwo enanLlomers of Lhe reacLanL produce a slngle
enanLlomer of producL
LNAN1ICUkL MLDICA1ICNS
O Advances ln lndusLrlal chemlcal processes have made lL economlcal for pharmaceuLlcal
manufacLurers Lo Lake drugs LhaL were orlglnally markeLed as a racemlc mlxLure and markeL Lhe
lndlvldual enanLlomers
O ln some cases Lhe enanLlomers have genulnely dlfferenL effecLs ln oLher cases Lhere may be no
cllnlcal beneflL Lo Lhe paLlenL ln some [urlsdlcLlons slngleenanLlomer drugs are separaLely
paLenLable from Lhe racemlc mlxLure lL ls posslble LhaL boLh enanLlomers are acLlve
O r lL may be LhaL only one ls acLlve ln whlch case separaLlng Lhe mlxLure has no ob[ecLlve
beneflLs buL exLends Lhe drugs paLenLablllLy
LNAN1ICSLLSC1IVI1 DkUG A8SCk1ICN DIS1kI8U1ICN ML1A8CLISM LkCkL1ICN
LNAN1ICSLLLC1IVI1 IN DkUG A8SCk1ICN
O 1he sLereoselecLlve naLure of some of Lhe processes occurrlng ln Au, may resulL ln
sLereolsomers exhlblLlng dlfferenL pharmacoklneLlc properLles
O ln absorpLlon Lhe raLes of absorpLlon of Lhe lndlvldual pure enanLlomers of drugs LhaL are
absorbed by acLlve LransporL may be dlfferenL
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

O lor example ()norgesLrel ls absorbed aL Lwlce Lhe raLe of (+)norgesLrel Lhrough buccal and
vaglnal membranes whllsL Ldopa ls more rapldly absorbed Lhan lLs enanLlomer udopa
O Powever absorpLlon of enanLlomers by passlve dlffuslon ls noL normally sLereoselecLlve so Lhe
raLes of absorpLlon of enanLlomers are usually ldenLlcal lurLhermore racemaLes may be
absorbed aL a dlfferenL raLe Lo Lhelr pure lndlvldual enanLlomers

LNAN1ICSLLLC1IVI1 IN DkUG DIS1kI8U1ICN
O SLereoselecLlvlLy appears Lo have llLLle lnfluence on Lhe LransporL of sLereolsomers Lhrough Lhe
clrculaLory sysLem
O Powever lL has been shown LhaL some enanLlomers preferenLlally blnd Lo a speclflc plasma
proLeln
O ln humans for example 8propanolol preferenLlally blnds Lo human albumln whlle Lhe S lsomer
prefers aacld glycoproLeln
O ln conLrasL sLereoselecLlvlLy may dependlng on Lhe mechanlsm of Lransfer lnfluence Lhe
movemenL of drugs across Lhe membranes separaLlng one body comparLmenL from anoLher
LNAN1ICSLLLC1IVI1 IN DkUG ML1A8CLISM
O ,any meLabollc processes are sLereoselecLlve
O onsequenLly sLereolsomers LhaL are meLabollsed by Lhese processes may exhlblL dlfferenL
behavlour paLLerns
O lor example Lhey mlghL llke Lhe enanLlomers of warfarln be meLabollsed by dlfferenL rouLes Lo
form dlfferenL meLabollLes (llg)
O AlLernaLlvely Lhelr ln vlvo sLablllLles may be dlfferenL lor example Lhe plasma halfllfe of S
lndacrlnone ls 23 hours buL Lhe value for Lhe 8 lsomer ls 1012 hours
O 1hese and oLher dlfferences beLween sLereolsomers are belleved Lo be ofLen due Lo Lhe
sLereospeclflc naLure of Lhe acLlons of Lhe enzymes lnvolved ln meLabollc processes
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE 8



SLCCNDAk nAkMACCLCGICAL IMLICA1ICNS CI ML1A8CLISM
,eLabollLes may be elLher pharmacologlcally lnacLlve or acLlve AcLlve meLabollLes may exhlblL a slmllar
acLlvlLy Lo Lhe drug a dlfferenL acLlvlLy or be Loxlc
Inact|ve metabo||tes
O 8ouLes LhaL resulL ln lnacLlve meLabollLes are classlfled as deLoxlflcaLlon processes
O lor example Lhe deLoxlflcaLlon of phenol resulLs ln Lhe formaLlon of phenyl hydrogen sulphaLe
whlch ls pharmacologlcally lnacLlve
O 1hls compound ls very waLer soluble and so ls readlly excreLed Lhrough Lhe kldney

Metabo||tes W|th A S|m||ar Act|v|ty 1o 1he Drug
O ln Lhls slLuaLlon Lhe meLabollLe can exhlblL elLher a dlfferenL poLency or duraLlon of acLlon or
boLh wlLh respecL Lo Lhe orlglnal drug
O lor example Lhe anxlolyLlc dlazepam whlch has a susLalned acLlon ls meLabollsed Lo Lhe
anxlolyLlc Lemazepam whlch has a shorL duraLlon of acLlon
STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE 9

O 1hls ln Lurn ls furLher meLabollsed by demeLhylaLlon Lo Lhe anxlolyLlc oxazepam whlch also has
a shorL duraLlon of acLlon


Metabo||tes w|th a d|ss|m||ar act|v|ty to the drug
ln Lhese cases Lhe acLlvlLy of a meLabollLe has no relaLlonshlp Lo LhaL of lLs parenL drug lor example Lhe
anLldepressanL lpronlazld ls meLabollsed by dealkylaLlon Lo Lhe anLlLuberculous drug lsonlazld

1ox|c Metabo||tes
1he Loxlc acLlon usually arlses because Lhe meLabollLe elLher acLlvaLes an alLernaLlve recepLor or acLs as
a precursor for oLher Loxlc compounds lor example deacylaLlon of Lhe analgeslc phenaceLln ylelds p
pheneLldlne whlch ls belleved Lo acL as Lhe precursor of subsLances LhaL cause Lhe condlLlon
meLhaemogloblnaemla 1hls condlLlon whlch causes headaches shorLness of breaLh cyanosls slckness
and faLlgue ls caused by Lhe presence of meLhaemoglobln (a modlflcaLlon of haemoglobln) ln Lhe blood
(llg) 9henaceLln ls also meLabollsed vla lLs nhydroxy derlvaLlve whlch ls belleved Lo cause llver
damage

STERE0CBENISTRY & BR0u ACTI0N

ABvANCEB NEBICINAL CBENISTRY PAuE

LNAN1ICSLLLC1IVI1 IN DkUG LkCkL1ICN
O A modesL sLereoselecLlvlLy has been reporLed ln Lhe renal excreLlon of a few drugs such as
chloroqulne plndolol and LerbuLallne

CCNCLUSICN
1he lncreaslng avallablllLy of slngleenanLlomer drugs promlses Lo provlde cllnlclans wlLh safer beLLer
LoleraLed and more efflcaclous medlcaLlons for LreaLlng paLlenLs lL ls lncumbenL upon Lhe pracLlclng
physlclan Lo be famlllar wlLh Lhe baslc characLerlsLlcs of chlral pharmaceuLlcals dlscussed ln Lhls arLlcle
ln parLlcular each enanLlomer of a glven chlral drug may have lLs own parLlcular pharmacologlc proflle
and a slngleenanLlomer formulaLlon of a drug may possess dlfferenL properLles Lhan Lhe racemlc
formulaLlon of Lhe same drug When boLh a slngleenanLlomer and a racemlc formulaLlon of a drug are
avallable Lhe lnformaLlon from cllnlcal Lrlals and cllnlcal experlence should be used Lo declde whlch
formulaLlon ls mosL approprlaLe