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Mol. Pharmaceutics,1!"# $% &'(# )**+, !*,!*)!-m.*/+**(h S!%+/&$/$+*/"*+**(&!Web Release Date:December !0# )**/
Copyright 2003 American Chemical Society
Molecular roperties o! W"# $ssential Drugs an%
ro&isional 'iopharmaceutical Classi!ication
(ehal A) *asim+ Marc Whitehouse+ Chan%rase,haran Ramachan%ran+ Mari&al
'erme-o+ "ans .ennern/s+ A-a S) "ussain+ "ans $) unginger+Salomon A)
Sta&chans,y+ *amal *) Mi%ha+ ino% ) Shah+ an% 4or%on .) Ami%on5
College of Pharmacy, University of Michigan, Ann Arbor, Michigan 4810910!", College
of Pharmacy, University of Ale#an$ria, Ale#an$ria, %gy&t, 'e&artment of Pharmacy an$(echnology, University of )alencia, )alencia, *&ain, 'e&artment of Pharmacy, +MC,
U&&sala University, *%"1 - U&&sala, */e$en, Center for 'rug %valuation an$
esearch, ffice of Pharmaceutical *cience, 2oo$ an$ 'rug A$ministration, oc3ville,Marylan$ -08", 'ivision of Pharmaceutical (echnology, ei$en5Amster$am Center for
'rug esearch, P.. +o# 9"0-, -00 A ei$en, (he 6etherlan$s, Pharmaceuticals
'ivision, College of Pharmacy, University of (e#as at Austin, Austin, (e#as 81-,Pharmaytics 7nc., 7nnovation Place, *as3atoon, *as3atche/an, Cana$a *6 -,
College of Me$icine, University of *as3atche/an, *as3atoon, *as3atche/an, Cana$a*6 "%", an$ College of Pharmacy an$ 6utrition, University of *as3atche/an,
*as3atoon, *as3atche/an, Cana$a *6 "C9
eceive$ *e&tember 1-, -00
Abstract:
The .ur.ose of this stud1 is to .rovisionall1 classif1# based on the 2io.harmaceutics
Classification S1stem 2CS"# drugs in immediate&release dosage forms that a..ear on the
3orld Health 4rgani5ation 3H4" 6ssential Drug 7ist, The classification in this re.ort is
based on the a8ueous solubilit1 of the drugs re.orted in commonl1 available referenceliterature and a correlation of human intestinal membrane .ermeabilit1 for a set of )'
reference drugs with their calculated .artition coefficients, The 3H4 6ssential Drug 7istconsists of a total of /)% medicines and )(* drugs# of which !)/ are oral drugs in
immediate&release 9:" .roducts, Drugs with dose numbers less than or e8ual to unit1
[Do ; ma
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(0? $)" were determined to be high&solubilit1 drugs, The classification of .ermeabilit1
is based on correlations of human intestinal .ermeabilit1 of )' reference drugs with the
estimated logPor C7ogP li.o.hilicit1 values, Meto.rolol was chosen as the referencecom.ound for .ermeabilit1 and logPor C7ogP, 7ogPand C7ogP were linearl1
correlated r); *,0$" for !*+ drugs, @ total of %/ +/,!?" and () %*,+?" drugs on the
3H4 list e,S, Food and Drug @dministration FD@",!This standard is based on ensuring thatabsor.tion is similar from the drug .roducts being com.ared and is based on the
fundamental .rocesses controlling the absor.tion .rocess, 9n this re.ort# we .rovisionall1
classif1 the oral immediate&release drug .roducts that a..ear on the 3orld Health
4rgani5ation 3H4" 6ssential Drug 7ist,
For an1 orall1 administered drug .roduct# the fundamental .arameters controlling the
drug absor.tion rate and e
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ensuring in vivobioe8uivalence,+The FD@ has recentl1 im.lemented the 2CS s1stem to
allow waiver of in vivobioavailabilit1 and bioe8uivalence testing of immediate&release
solid dosage forms for Class ! high&solubilit1# high&.ermeabilit1 drugs,!3aivers forClass / high&solubilit1# low&.ermeabilit1" drugs are scientificall1 ustified and have been
recommended,%#(Such waivers have the .otential to both decrease the cost and im.rove
the 8ualit1 of medicines,
Since !'00# the 3H4 has .rovided a Ecore listE of minimum medicines re8uired for basichealth care, Such essential medicines are selected on the basis of .ublic health relevance#
efficac1# safet1# and cost&effectiveness, @ total of )(* drugs are included in the !)th
edition of the 3H4 list#0!)/ of which are orall1 administered, For com.arison# theannual list of the to. )** .rescribed drugs in the >nited States >,S," includes !+! orall1
administered drugs#$+/ of which are also on the 3H4 list,
This re.ort is focused on orall1 administered drugs included in the 3H4 6ssential Drug
7ist, Select com.arisons to the immediate&release drug .roducts in the to. )** >,S, drug
list are also included, @ com.arison of the to. >,S,# 6uro.ean# and Ja.anese drug listswill be .resented in a future .ublication, The classification of drug solubilit1 is based on
the dimensionless dose number# Do,'Do is the ratio of drug concentration in theadministered volume )%* m7" to the saturation solubilit1 of the drug in water [Do ;
dose-)%*"-solubilit1], 9deall1# classification of drug .ermeabilit1 would be based on
e
Ma7imum Dose Strength)For 3H4 oral drugs formulated in immediate&release dosage
forms# values for ma
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whereM*is the highest dose strength milligrams"# Csis the solubilit1 milligrams .er
milliliter"# and )*; )%* m7,
artition Coe!!icients)7ogPn&octanol-water .artition coefficient" values were
calculated using three different fragmentation methods that are based on atomic
contributions to li.o.hilicit1,!0&!'C7ogP values were calculated using the C7ogP .rogramversion /,*" from 2io21te Cor., Claremont# C@" generated with algorithms based on
theoretical treatments develo.ed b1 7eo,)*6stimates of logPas well as C7ogP for the
uncharged solute molecule were obtained using ChemDraw >ltra (,* CambridgeSoft
Cor.,# Cambridge# M@" and chemical structures of the drug as de.icted in the Merc=9nde
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Distribution o! Drug 8herapeutic Class)The .ercentage of anti&infective drugs on the
3H4 oral 6ssential Medicines 7ist was significantl1 higher than that on the to. )** >,S,
list ++,0? vs !0,0?"# reflecting their greater need in develo.ing nations, @ brea=downcom.arison of the anti&infective drugs on the two lists is shown in Figure !, 4f the other
maor thera.eutic classes# a significantl1 higher .re.onderance of antih1.ertensive#
antide.ressant# an,S, list than on the 3H4 list Figure )",
Classi!ication o! Drug Solubility)Figure / shows a com.arison .lot of the .ercentage of
drugs on the two lists in various solubilit1 categories, Drugs with dose numbers of !
were classified as high&solubilit1 drugs, Conversel1# drugs with dose numbers of G! wereclassified as low&solubilit1 drugs, 4n the basis of these criteria# $) of the !)/ 3H4 oral
drugs (0?" and '( of the >,S, oral drugs ($?" were classified as high&solubilit1 drugs,
9t is also evident from Figure / that the solubilit1 distribution of the drugs on the 3H4list is 8uite similar to that of the >,S, list, Dose number calculations using the lowest dose
strength of the 3H4 oral drugs revealed that $' of the !)/ 3H4 drugs 0),+?" were
classified as high&solubilit1 drugs, Thus# seven drugs changed solubilit1 classificationlow to high solubilit1" when dose numbers were calculated using the drugs lowest dose
strength,
Figure / Com.arison of the solubilit1 classification of drugs on the 3H4 and>,S, lists,
Criteria !or Classi!ication o! ermeability)The classification of .ermeabilit1 of the
!)/ oral drugs was based on correlations of eltra (,*, Thisset of drugs includes !+ com.ounds that are listed in the FD@ 3aiver Iuidance as
recommended drugs for .ermeabilit1 classification,!@ .lot of the e
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4f the eight drugs that were classified as low&.ermeabilit1 drugs rather than high&
.ermeabilit1 drugs as determined e
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'CS Classi!ication o! $ssential W"# 6mme%iateRelease #ral Drugs)The !)/ oral
drugs in immediate&release dosage forms on the 3H4 6ssential Medicines 7ist were
.rovisionall1 classified into the 2CS classes on the basis of dose number and logPordose number and C7ogP, The 2CS classification of the 3H4 drugs on the basis of dose
number and log'was not attem.ted because of the limited availabilit1 of .avalues
from reference sources, 7ogPand C7ogP estimates for !*+ and !!( of the !)/ drugs#res.ectivel1# were available and allowed a more com.rehensive .rovisional 2CS
classification, 7ogPand C7ogP values were fairl1 linearl1 related r); *,0$" for !*+
drugs however# do
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between the >,S, and the develo.ing countries, Since the focus of this re.ort is to .rovide
a classification of oral drugs in immediate&release dosage forms contained on the 3H4
6ssential Medicines 7ist# the molecular descri.tors listed in Tables ) and / were obtainedfrom reference data sources that are widel1 used and are easil1 accessible,
The 2CS classification of the 3H4 medicines was conducted using two criteria, Thefirst# a solubilit1 classification# was based on the calculated dose number, Drugs were
categori5ed as EsolubleE if the1 had a dose number of !, The finding that (0? of thedrugs on the 3H4 list and ($? on the to. )** >,S, list were classified as Ehigh&
solubilit1E drugs suggests that maor differences in drug 2CSclassification of the two lists
are unli=el1, The high&solubilit1 classification is li=el1 conservative# considering thatconservative estimates of solubilit1 were ado.ted in this re.ort, @ total of +/ drugs on the
3H4 list and +' drugs on the >,S, list eSP or Merc= 9nde< as
.racticall1 insoluble was slightl1 higher on the >,S, list /' drugs" than on the 3H4 list/* drugs", @ccording to the >SP# for drugs defined as .racticall1 insoluble .i"# the
solubilit1 is less than *,! mg-m7, However# in this stud1# a more conservative solubilit1
estimate of *,*! mg-m7 was a..lied to calculate the dose number of .i drugs, Furtherliterature investigation into the solubilit1 of .racticall1 insoluble drugs)).rovided a
numerical value for onl1 !' of the /* drugs on the 3H4 list# and onl1 !( of the /' .i
drugs on the >,S, list, Conflicting literature solubilit1 data were found for drugs such as
carbama5e.ine and n1statin that were on both lists# resulting in highl1 variable solubilit1and dose number estimation for these two drugs, @ com.arison of dose number
classification based on literature estimates with those obtained using a conservative valueof *,*! mg-m7 indicated agreement for !% of the remaining !0 drugs on the 3H4 listand !) of the !+ drugs on the >,S, list, The e
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E.ermeableE drugs, Meto.rolol was chosen as the reference com.ound for .ermeabilit1
since '%? of the drug is =nown to be absorbed from the gastrointestinal tract,
@n e
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drug .roducts ma1 be based on a suitable in vitrodissolution test .rocedure, 4n the basis
of solubilit1 alone# (0? of the drugs were high&solubilit1 drugs# re.resenting the
.otential number of drugs that ma1 be eligible for in vitro26 testing and biowaivers, Thedifference between the two .ercentages %% vs (0?" can be attributed to the inabilit1 to
obtain .ermeabilit1 estimates,
9n summar1# .rovisional 2CS classification of the drugs contained on the 3H4 6ssential
Medicines 7ist suggests that the maorit1 of the drug .roducts contained on the 3H4 listare candidates for waiver of in vivobioe8uivalence testing based on an in vitro
dissolution test EbiowaiverE, @ccording to the FD@ Iuidance!for biowaivers# the test
.roduct should dissolve $%? in /* min b1 the >SP 9 bas=et" dissolution test at !**r.m or the >SP 99 .addle" dissolution test at %* r.m in '** m7 of *,! L HCl# .H +,%#
and .H (,$ buffers and should meet the f) criteria of %*, For ver1 ra.id dissolution#
$%? in !% min# f) criteria are not re8uired, The im.act of waiver of in vivobioe8uivalence 26" testing and its re.lacement with ra.id and affordable dissolution
standards in develo.ing countries is e
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Pharma71tics 9nc, and >niversit1 of Sas=atchewan,
!, 3aiver of7n )ivo2ioavailabilit1 and 2ioe8uivalence Studies for 9mmediate&:elease
Solid 4ral Dosage Forms 2ased on a 2io.harmaceutics Classification S1stem# )**),2'A ui$ance for 7n$ustry Federal Drug and Food @dministrationA :oc=ville# MD#
)**),
), @midon# I, 7, 7ennernas# H, Shah# , P, Crison# J, :, @ Theoretical 2asis for a
2io.harmaceutic Drug ClassificationA The Correlation of7n )itroDrug ProductDissolution and7n )ivo2ioavailabilit1,Pharm. es, 1
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Theoreticall1 Derived Parameters, @ Multivariate Data @nal1sis @..roach,:,Me$.
Chem.1
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MD:! and Caco&) cell monola1ers,+r. :. Pharmacol.2000# 1-9# !)/%&!)+/,
[ChemPort][Medline]
)+, Morsing# P, @dler# I, 2randt&6liasson# >, Bar.# 7, 4hlson# B, :enberg# 7,SW8uist# P,&4, @brahamson# T, Mechanistic differences of various @T!&rece.tor bloc=ers
in isolated vessels of different origin,
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aceta5olamide )%* vss *,! !* &!,!/*,!
+0,)
antiglaucoma
# diuretic+ +
acetylsalicylicaci$
%** ss# /** /,// 0.601 !,*) !,!$
/,%
LS@9Ms#
antithrombol1tic
/ /
acyclovir )** s.s !* 0.08 &),+)
&
!,%
'
antiviral
anti&her.es"/ /
albenda5ole +** .i 0)01 !(* /,+(),%
%
anthelminthi
c Cesto$es") )
allo&urinol !** vss *,! + *,(/*,/)
!*,) antiurolithic + +
amiloride
h1drochloride% ss ! 0.02 &*,%%
&
*,0
/
$,0 diuretic / /
amitri&tylinehy$rochlori$e
)% fs !** 0.001 +,$%+,+)
',+an
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ben5nida5ole !** *,+ 1.0 *,'*
anti.roto5oal
(ry&anosom
a"
/
bi.eridenh1drochloride
) ss ! 0.008 +,+)/,%(
anti.ar=insonian
! !
ca&to&ril )% fs !** 0.001 *,$'*,)
+
/,0#
',$
antih1.ertens
ive/ /
carbama=e&in
e)** .i 0)01 $* !,'$
),'
/0,*
anticonvulsa
nt#
antie.ile.tic
) )
chloram.henic
ol)%* ss ),% 0.40 !,)$
&*,)
/
antibacterial / /
chloro8uine
.hos.hate!%* fs !** 0.006 %,*(
/,0
/
antimalarial#
antiamebic! !
chlor.heniramine maleate
+ fs !(* 0.0001 /,!%/,()
',)antihistaminic
! !
chlor.roma5ine
h1drochloride
!** vs !*** 0.000 %,$*+,)
+
antiemetic#
anti.s1chotic! !
cimeti$ine )** ss ! 0.80 *,/%*,0
'(,$
antiulcerativ
e/ /
ci&roflo#acinhy$rochlori$e
)%* s.s !* 0.1 &!,!%!,/)
antibacterial / /
clofa5imine !** .i 0)01 +* 0,%* %,/'
$,/0#$,%!
antibacterialle.rostatic"
) )
clomi.hene
citrate%* ss ! 0.20 0,!% (,0
gonad&
stimulating.rinci.le
! !
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clomi.ramine
h1drochloride)% fs !** 0.001
antiobsession
al agent
clo
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D7&methionine )%* s // 0.030s.ecific
antidote
$o#ycycline !** vss *,! + &*,(*
&
/,((
antibacterial#antimalarial
+ +
efaviren5 )** .i 0)01 $* +,'%/,(
$!*,) antiviral ) )
ergometrine
maleate*,) ss !*
0.0000
8!,)/
*,/
%(,$ o
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drug
ma
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bu.ro.ion
h1drochloride!** /!) 0.001 0,' antide.ressant
bus.irone
h1drochloride /* vs !*** 0.0001
!,))#
0,/) an
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clindam1cin
h1drochloride/** fs !** 0.012 0,( antibacterial
clona5e.am ) .i 0)01 0.8
!,%#
!*,% anticonvulsant
clonidineh1drochloride
*,/ s $*0.00001
5antih1.ertensive#analgesic
clo.idogrel bisulfate 0% !** 0.003 antithrombotic
co$eine &hos&hate (* fs !** 0.0024aarcotic analgesic#antitussive
c1cloben5a.rine
h1drochloride!* fs !** 0.0004 $,+0
s=eletal muscle
rela
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ethinyl estra$iol *,% .i 0)01 0.2estrogen
contrace.tive"
famotidine +* vss *,! !,( 0,! antiulcerative
fenofibrate )** .i 0)01 $*antih1.erli.o.roteinem
ic
fe
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bitartrate analgesic#antitussive
h1dro
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medro
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creatinine &*,(/ &!,00 *,)' c c
desi.ramine /,'+ +,+0 +,%* c c
D&glucose &/,%) &/,)0 !*,** fn fn
enala.ril !,00 *,(0 !,%0 c fn
enala.rilat !,!0 *,$$ *,)* c c
fluvastatin /,+! +,*% ),+* c c
furosemide *,0+ !,'* *,*% c f.
h1drochlorothia5ide &*,!% &*,/( *,*+ c c
=eto.rofen /,/! ),0( $,0* c c
7&do.a &),/' &),$) /,+* fn fn
lisino.ril *,'! &!,(' *,// c c
7&leucine &!,() &!,(0 (,)* fn fn
losartan na +,!! !,!% na f.
meto.rolol !,0) !,/% !,/+ ref ref
na.ro
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terbutaline !,!( *,%( *,/* c c
valac1clovir &!,*( &!,)) !,(( fn fn
vera.amil %,(' +,+0 (,$* c c
a@bbreviationsA c# correct fn# false negative f.# false .ositive ref# reference na# notavailable,
Table %, .a# 7og'# and Human Jeunal Permeabilit1 of :eference Drugsa
drug .alog'at .H(,%
human .ermeabilit1 X!*+cm-s"
.ermeabilit1classification
anti.1rine !,+ !,*! %,(* c
atenolol ',( &),(* *,)* c
carbama5e.ine L9 ),'/ +,/* c
cimetidine (,$ *,/! *,)( f.
creatinine +,'b &),)' *,)' c
desi.ramine !*,) *,)+ +,%* c
fluvastatin +,/b !,)) ),+* c
furosemide /,' &!,$( *,*% c
h1drochlorothia5ide ',) &),$% *,*+ c
=eto.rofen +,% !,/! $,0* c
losartan +,0c !,(' !,!% f.
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meto.rolol ',0 &!,+$ !,/+ ref
na.ro
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h1drala5ine
h1drochloride%* s# )% +* 0.005 !,*)
*,0
/0,/
antih1.erten
sive/ /
hy$rochlorothia=i$e
%* ss ! 0.2 &*,/(
&
*,!%
0,'#',)
diuretic#
antih1.ertensive
/ /
ibu&rofen +** .i 0)01 !(* /,($/,!
+%,)
LS@9M#
analgesic#
anti.1retic
) )
indinavir
sulfate+** vs !***
0.001
6/,($
),+
'antiviral ! !
isonia5id /** fs# $ !)% 0.01 &*,(0*,(
+
antibacterialtuberculosta
tic"
/ /
9vermectin ( *,**+ (
anthelminthi
cnchocerca
"
lamivudine !%* 0*0.008
6&!,+(
*,*
(antiviral / /
levamisoleh1drochloride
!%* fs !** 0.006 !,$+),0'
anthelminthi
cnematodes"
! !
levo$o&a )%* ss ! 1.0 &),$)anti.ar=inso
nian/
levonorgestrel *,0% .i 0)01 0.3 /,/!
/,*
(
.rogestogen
contrace.tive"
! !
levothyro#ineso$ium
*,! vss *,!% 0.003 /,%!0,/
(
th1roid
hormone! !
lithium /** s.s !* 0.12 antimanic
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carbonate
lo.inavir with
ritonavir"!//,/ 0)01 %/,/ (,!*
+,%
(antiviral ) )
lumefantrine
withartemether"
!)* ! 0.48 !*,)*$,$
!antimalarial ! !
mebenda5ole
chewable"%** .i 0)01 )** /,*$
),%
*
anthelminthic
nematodes"
) )
meflo8uine
h1drochloride )%* ss ! 1.00 /,(0
+,!
) antimalarial ! !
metforminhy$rochlori$e
%** fs !** 0.02 &!,(/*,!%
!),+ antidiabetic / /
methotre
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bromide 06 'muscle
rela
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&henytoin
>che/able?%* .i 0)01 )* ),*'
),!
+
$,*(&
$,//
anticonvulsa
nt#
antie.ile.tic
) )
&henytoinso$ium
!** fs !** 0.004 ),*'),!+
anticonvulsant#
antie.ile.tic
! !
.ra5i8uantel (** vss *,+ ( /,/(),*
)
anthelminthi
c
*chistosoma"
) )
&re$nisolone % vss *,! 0.2 /,%*),%
!
glucocorticoi
d#antiallergic
! !
.rima8uine.hos.hate
!% s# !% ((,00.000
9),(*
!,+0
antimalarial / !
.roguanil
h1drochloride!** ss ! 0.40 ),%/
/,!
0antimalarial ! !
&rometha=ine
hy$rochlori$e)% vs !***
0.000
1+,'*
/,'
*',!
antihistamini
c# antiemetic! !
&ro&ranolol
hy$rochlori$e+* s // 0.00 ),0%
),(
%
migraine
.ro.h1la
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bromidemuscle
rela
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sa8uinavir
mes1late)** ),)) 0.36 +,0/
),0
/antiviral ! !
Senna
Sennoside@Y2"
0,% s# /% )$,( 0.001 cathartic
s&ironolactone
)% .i 0)01 !* ),)%),'
*diuretic ) )
stavudine +* $/ 0.002 &*,0/
&
*,+
0
antiviral / /
sulfadia5ine %**.i#!/***
*,*$ )% *,!**,)!
antibacterial + +
sulfametho#a
=ole+** .i 0)01 !(* *,%(
*,$
(antibacterial + +
sulfasala5ine %** .i 0)01 )** /,$$/,+
)
I9 anti&
inflammator1#DM@:Ds
) )
theo.h1lline /** ss ! !,) &*,*/&!,*
/
$,00#!/,%#
!!,%
bronchodilator + +
triclabenda5o
le)%* (,++
%,+
+
anthelminthic
fasciola"
trimetho&rim )** vss *,+ ) *,'$!,+/
(,( antibacterial + +
val.roic acid %** ss !,/ !,%+ ),0( ),+)
+,$ anticonvulsant#antimanic
/ /
vera&amil
hy$rochlori$
e$* s $/ 0.004 +,+0
%,(
'$,(
antianginal#
antiarrh1thmic! !
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/arfarin
so$ium% vs !***
0.000
02),'*
),'
0anticoagulant ! !
5idovudine /** )*,! 0.06 *,*+ antiviral /
aDrugs in italics common to both 3H4 and to. )** >,S, lists,bPracticall1 insoluble .i"
drugs given in bold,calues in bold italics indicate dose numbers of !,*,
Table / Continued
drug
ma
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norgestimate *,)% .i 0)01 0.1 oral contrace.tive
nortri.t1line
h1drochloride0% s // 0.009 ',0/ antide.ressant
nystatin !** .i + 0.1 antifungal
olan5a.ine )* .i 0)01 $ anti.s1chotic
o
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.ro.o
7/25/2019 Nice article for BCS
36/37
s&ironolactone !** .i 0)01 +* diuretic
sulfametho#a=ole $** .i 0)01 /)* antibacterial
sumatri.tan
succinate!** s !** 0.004 antimigraine
tamo
7/25/2019 Nice article for BCS
37/37
',+
valdeco