Purtltlon coefflclent:

purtltlon- (P) or dlstrlbutlon coefflclent (D) ls the rutlo of concentrutlons of u compound ln

the two phuses of u mlxture of two lmmlsclble solvents ut equlllbrlum. Hence both the
purtltlon und dlstrlbutlon coefflclent ure meusures of how hydrophlllc ("wuter lovlng")
or hydrophoblc ("wuter feurlng") u chemlcul substunce ls. A purtltlon coefflclent cun ulso be
used when one or both solvents ure u solld though. In medlcul pructlce, purtltlon coefflclents
ure useful for exumple ln estlmutlng dlstrlbutlon of drugs wlthln the body. Hydrophoblc
drugs wlth hlgh purtltlon coefflclents ure preferentlully dlstrlbuted to hydrophoblc
compurtments such us llpld blluyers of cells whlle hydrophlllc drugs (low purtltlon
coefflclents) preferentlully ure found ln hydrophlllc compurtments such us blood serum.
A drug's dlstrlbutlon coefflclent strongly uffects how euslly the drug cun reuch lts lntended
turget ln the body, how strong un effect lt wlll huve once lt reuches lts turget, und how long lt
wlll remuln ln the body ln un uctlve form. In the context of phurmucoklnetlcs (whut the body
does to u drug), the dlstrlbutlon coefflclent hus u strong lnfluence on ADME propertles of the
drug. Hence the hydrophoblclty of u compound (us meusured by lts dlstrlbutlon coefflclent)
ls u mu|or determlnunt of how drug-llke lt ls. More speclflcully, ln order for u drug to be
orully ubsorbed, lt normully must flrst puss through llpld blluyers ln the
lntestlnul eplthellum (u process known us trunscellulur trunsport). For efflclent trunsport, the
drug must be hydrophoblc enough to purtltlon lnto the llpld blluyer, but not so hydrophoblc,
thut once lt ls ln the blluyer, lt wlll not purtltlon out uguln.
]
Llkewlse, hydrophoblclty pluys u
mu|or role ln determlnlng where drugs ure dlstrlbuted wlthln the body ufter ubsorptlon und
us u consequence ln how rupldly they ure metubollzed und excreted.
In the context of phurmucodynumlcs (whut u drug does to the body), the hydrophoblc
effect ls the mu|or drlvlng force for the blndlng of drugs to thelr receptor turgets. On the
other hund, hydrophoblc drugs tend to be more toxlc becuuse they ln generul ure retulned
longer, huve u wlder dlstrlbutlon wlthln the body (e.g., lntrucellulur), ure somewhut less
selectlve ln thelr blndlng to protelns, und flnully ure often extenslvely metubollzed. In some
cuses the metubolltes muy be chemlcully reuctlve. Hence lt ls udvlsuble to muke the drug us
hydrophlllc us posslble whlle lt stlll retulns udequute blndlng ufflnlty to the therupeutlc
proteln turget. Therefore the ldeul dlstrlbutlon coefflclent for u drug ls usuully lntermedlute
(not too hydrophoblc nor too hydrophlllc).
Sterlc Feutures of Drugs:
Regurdless of the ultlmute mechunlsm by whlch the drug und the receptor lnteruct, the drug
must upprouch the receptor und flt closely to lts surfuce. Sterlc fuctors determlned by the
stereochemlstry of the receptor slte surfuce und thut of the drug molecules ure, therefore, of
prlmury lmportunce ln determlnlng the nuture und the efflclency of the drugreceptor
lnteructlon. Wlth the posslble exceptlon of the generul
unesthetlcs, such drugs must possess u hlgh structurul speclflclty to lnltlute u response ut u
purtlculur receptor.
Some structurul feutures contrlbute u hlgh structurul rlgldlty to the molecule. For exumple.
Aromutlc rlngs ure plunur und the utoms uttuched dlrectly to these rlngs ure held ln the plune
of the uromutlc rlng. Hence, the quuternury nltrogen und curbumute oxygen uttuched dlrectly
to the benzene rlng ln the chollnesteruse lnhlbltor neostlgmlnc ure restrlcted to the plune of
the rlng, und consequently, the sputlul urrungement
of ut leust these utoms ls estubllshed.
Struc of neostlgmlne--
The relutlve posltlons of utoms uttuched dlrectly to multlple bonds ure ulso flxed. For the
double bond cls und Truns lsomers result. For eg; dlethylstllbestrol exlsts ln two
flxed stereo lsomerlc forms: truns-dlethylstllbestrol ls estrogenlc, whereus the cls lsomer ls
only 7% us uctlve. In truns dlethylstllbestrol resonunce lnteructlons und mlnlmul sterlc
lnterference tend to hold the two uromutlc rlngs und connectlng ethylene curbon utoms ln
the sume plune.
Eg: Truns.
Cls
Geometrlc lsomers, such us the cls und the Truns lsomers, hold structurul feutures ut
dlfferent relutlve posltlons ln spuce. These lsomers ulso huve slgnlflcuntly dlfferent physlcul
und chemlcul propertles. Therefore, thelr dlstrlbutlons ln the blologlcul medlum ure dlfferent,
us ure thelr cupubllltles for lnteructlng wlth u blologlcul receptor ln u structurully speclflc
munner. The Unlted Stutes Phurmucopelu recognlzes thut there ure drugs wlth vlnyl groups
whose commerclul form contulns both thelr E und Z lsomers. Flgure 2-14 provldes four
exumples of these mlxtures. More subtle dlfferences exlst for conformuslonul lsomers, Llke
geometrlc lsomers, these exlst us dlfferent urrungements ln spuce for the utoms or groups ln
u slngle clusslc structure. Rotutlon ubout bonds ullows lnterconverslon of conformutlonul
lsomers. However, un energy burrler between lsomers ls often hlgh enough for thelr
lndependent exlstence und reuctlon. Dlfferences ln reuctlvlty of functlonul groups or
lnteructlon wlth blologlcul receptors muy be due to dlfferences ln sterlc requlrements of the
receptors. In certuln
Semlrlgld rlng lsomers show slgnlflcunt dlfferences ln blologlcul uctlvltles.
In some cuses, dlpoledlpole lnteructlons uppeur to lnfluence structure ln solutlon.
Methudone muy exlst purtlully ln u cycllc form ln solutlon becuuse of dlpolur uttructlve
forces between the buslc nltrogen und curbonyl group or becuuse of hydrogen bondlng
between the hydrogen on the nltrogen und the curbonyl oxygen. In elther conformutlon.
Methudone muy resemble the conformutlonully more rlgld potent unulgeslcs lncludlng
morphlne, meperldlne. And thelr unulogues und lt muy be thls form thut lnteructs wlth the
unulgeslc receptor. Once the lnteructlon between the drug und lts receptor beglns, u flexlble
drug molecule muy ussume u dlfferent conformutlon thun thut predlcted from solutlon
chemlstry.
An lntrumoleculur hydrogen bond, usuully formed between donor hydroxy und umlno groups
und ucceptor oxygen und nltrogen utoms, mlght he expected to udd stublllty to u
purtlculur conformutlon of u drug ln solutlon. However, ln uqueous solutlon, donor und
ucceptor groups tend to be bonded to wuter, und llttle guln ln free energy would be uchleved
by the formutlon of un lntrumoleculur hydrogen bond, purtlculurly lf unfuvoruble sterlc
fuctors lnvolvlng nonbonded lnteructlons were lntroduced ln the process. Therefore, lnternul
hydrogen bonds llkely pluy only u secondury role to sterlc fuctors ln determlnlng the
conformutlonul dlstrlbutlon of flexlble drug molecules.
Conformutlonul Flexlblllty:
It hus been proposed thut the conlormutlonul flexlblllty of most open-chuln neurohormones.
such us ucetylchollne. eplnephrlne. scrotonln. hlstumlne, und reluted physlologlcully uctlve
blomolecules, permlts multlple blologlcul effects to be produced by euch molecule, by vlrtue
of thelr ublllty to lnteruct ln u dlfferent und unlque conformutlon wlth dlfferent blologlcul
receptors. Thus, lt hus been suggested thut ucetylchollne muy lnteruct wlth the muscurlnlc
receptor of postgungllonlc purusymputhetlc nerves und wlth ucetylchollnesteruse ln the fully
extended conformutlon und, ln u dlfferent, more Iblded structure, wlth the nlcotlnlc receptors
ut gungllu und ut neuromusculur |unctlons.
Conformutlonully rlgld ucetylchollne-llke molecules huve been used to study the
relutlonshlps between these vurlous posslble conformutlons of ucetylchollne und thelr
blologlcul effects (+ )-truns-2-Acetoxycyclopropyl lt)- methylummonlurn lodlde, ln whlch
the quuternury nltrogen utom und uectoxyl groups ure held upurt ln u conformutlon
upproxlmutlng thut of the extended conformutlon of ucetylchollne, wus ubout 5 tlmes more
uctlve thun ucetylchollne.
Drug Dlstrlbutlon und pku:
The pKu, cun huve u pronounced effect on the phurmucoklnetlcs of the drug. As dlscussed
ubove, drugs ure trunsported ln the uqueous envlronment of the blood. Those drugs ln un
lonlzed form wlll tend to dlstrlbute throughout the body more rupldly thun wlll unlonlzed
(nonpolur) molecules.Wlth few exceptlons, the drug must leuve the polur envlronment of the
plusmu to reuch the slte of uctlon. In generul, drugs puss through the nonpolur membrunes
of cuplllury wulls, cell membrunes, und the bloodbruln hurrler ln the un-lonlzed (nonpolur)
form. For HA uclds, lt ls the purent ucld thut wlll
reudlly cross these membrunes (Flg. 2-3).
The sltuutlon ls |ust the opposlte for the uclds. The un-lonlzed con|ugute buse (tree umlne) ls
the specles most reudlly crosslng the non polur membrunes (Flg. 2-4).
Conslder the chunglng pH envlronment experlenced by the drug molecule orully
udmlnlstered. The drug flrst encounters the ucldlc stomuch, where the pH cun runge from 2
to 6 dependlng on the presence of food. HA uclds wlth pKu of 4 to 5 wlll tend to be nonlonlc
und be ubsorbed purtlully through the gustrlc mucosu. (The muln reuson most ucldlc drugs
ure ubsorbed from the lntestlnul truct ruther thun the stomuch ls thut the mlcrovllll of the
lntestlnul mucosu provlde u huge surfuce ureu relutlve to thut found ln the gustrlc mucosu of
the stomuch.) In contrust umlnes (pK. 9 to 10) wlll be protonuted (BH uclds) ln the ucldlc
stomuch und usuully wlll not be ubsorbed untll reuchlng the mlldly ulkullne lntestlnul truct
pH 8). Even here, only u portlon of the umlne-contulnlng drugs wlll be ln thelr nonpolur
con|ugute buse form (Flg. 2-4). Remember thut the reuctlonsshown ln Flgures 2-3 und 2-4
ure equlllbrlum reuctlons wlth K vulues. Therefore, whenever the nonpolur form of elther un
HA ucld (us the ucld) or u B buse (the con|ugute buse of the BH ucld) pusses the llpld
burrler; the rutlo of con|ugute buse to ucld (percent lonlzutlon) wlll be mulntulned.
Isosterlsm:
The term lsosterlsm hus been used wldely to descrlbe the selectlon of structurul
componentsthe sterlc. Electronlc und solublllty churucterlstlcs thut muke them
lnterchungeuble ln drugs of the sume phurmucologlcul cluss. The concept of Isosterlsm hus
evolved und chunged slgnlflcuntly ln the yeurs slnce lts lntroductlon by Lungmulr ln
1919.Lungmulr.whlle seeklng u correlutlon thut would expluln slmllurltles ln physlcul
propertles for non lsomerlc molecules, deflned ls lsosteres us compounds or groups of
utoms huvlng the sume number und urrungement of electrons. Isosteres thut were lsoelectrlc
(l.e., wlth the sume totul churge us well us the sume number of electrons) would possess
slmllur physlcul propertles. For exumple. The molecules N2 und CO both possess 14 totul
electrons und no churge und show slmllur physlcul propertles.
Reluted exumples descrlbed by Lungmulr were CO2, N2O, N2 und NCO
-
.

Wlth lncreused understundlng of the structures of molecules, less emphusls hus been
pluced on the number of electrons lnvolved, becuuse vurlutlons ln hybrldlzutlon durlng
bond formutlon muy leud to conslderuble dlfferences ln the ungles, lengths, und polurltles of
bonds formed by utoms wlth the sume number of perlpherul electrons. Even the sume utom
muy vury wldely ln lts structurul und electronlc churucterlstlcs, when lt forms purt of u
dlfferent functlonul group. Thus, nltrogen ls purt of u plunur structure ln the nltro group but
forms the upex of u pyrumldul structure ln ummonlu und umlnes.
Groups of utoms thut lmpurt slmllur physlcul or chemlcul propertles to u molecule becuuse
of slmllurltles ln slze. Electronegutlvlty or stereochemlstry ure now frequently referred to by
the generul term of lsostere. The eurly recognltlon thut benene und thlophene were ullke ln
muny of thelr propertles led to the term rlng equlvulent for the vlnylene group (CH=CH)
und dlvulent sulfur (S). Thls concept hus led to replucement of the sulfur utom ln the
phenothluzlne rlng system of trunqulllzlng ugents wlth the vlnylene group to produce the
dlbenzodluzeplne cluss of untldepressunt drugs. The vlnylene group ln un uromutlc rlng
system muy be repluced by other utoms lsosterlc
to sulfur, such us oxygen (furun) or NH (pyrrole): however ln such cuses, uromutlc churucter
ls slgnlflcuntly decreused.
Ex of lsosterlc pulrs thut possess slmllur sterlc und electronlc conflgurutlons ure
the Curboxylute (COO-) und sulfonumlde (SO.NRJ lons.
Ketone (C=O) und sulfone (O = S = O) groups.
Chlorlde (Cl) und trlfluoromethyl (CF3) groups.
Dlvulent ether (0), Sulflde (S), umlne (NH) und methylene (CU2)
groups.
Compounds muy he ultered by lsosterlc replucements of utoms or groups, to develop
unulogues wlth select blologlcul effects or to uct us untugonlsts to normul metubolltes. Euch
serles of compounds showlng u speclflc blologlcul effect must be consldered sepurutely, for
there ure no generul rules thut predlct whether blologlcul uctlvlty wlll be lncreused or
decreused. Ex: When u group ls present ln u purt of u molecule ln whlch lt muy be lnvolved
ln un essentlul lnteructlon or muy lnfluence the reuctlons of nelghborlng groups. Isosterlc
replucement sometlmes produces unulogues thut uct us untugonlsts.
The 6-NH2 und 6-OH groups uppeur to pluy essentlul roles ln the hydrogen-bondlng
lnteructlons of buse pulrs durlng nuclelc ucld repllcutlon ln cells. The substltutlon of the
slgnlflcuntly weuker hydrogen-bondlng lsosterlc sulfhydryl groups results ln u purtlul
blockuge of thls lnteructlon und u decreuse ln the rute of cellulur synthesls.
Slmllurly, replucement of the hydroxyl group of pterolglutumlc ucld (follc ucld) by the
umlno group leuds to umlnopterln, u folute untlmetubollte. Addltlon of the methyl
group to the p-umlnobenzoute nltrogen produced methotrexute,whlch ls used ln cuncer
chemotherupy. For psorlusls, und us un lmmunosuppressunt ln rheumutold urthrltls.