APPLIED BIOPHARMACEUTICS

Prof. Dr. Suwaldi Martodihardjo, M.Sc., A t !acult" of Phar#ac" $adjah Mada U%i&'r(it" )o*ja+arta R'f'r'%c'(, -. Shar*'l, L., .u/Po%*, S., 0u, A.B.C., 1223, Applied Biopharmaceutics & Pharmacokinetics, 3th Ed., Mc$raw/Hill, Bo(to%. 1. Rit(ch'l, ..A., 4'ar%(, $.L., 1225, Handbook of Basic Pharmacokinetics Including Clinical Applications, 6th Ed., APhA, .a(hi%*to%, D.C. 7. .a(hi%*to%, 8., .a(hi%*to%, C., .il(o%, C.$., 122-, Physiological Pharmaceutics Barriers to Drug Absorption, 1%d Ed., Ta"lor 9 !ra%ci(, 8'w 0or+. 5. Dr'((#a%, ).B., L'%%'r%a(, H., 1222, ral Drug Absorption Prediction and Assessment, Marc'l D'++'r, 8'w 0or+. 3. Ba%+'r, $.S., Rhod'(, C.T., -::6, !odern Pharmaceutics, 7rd Editio%, R'&i('d a%d E; a%d'd, Marc'l D'++'r, 8'w 0or+. 6. $'%%aro, A.R., 1222, "emington# $he %cience and Practice of Pharmacy, 12th Editio%, Li i%cott .illia#( 9 .il+i%(, Philad'l hia.

Th' d't'r#i%a%t( of th' i%/&i&o 'rfor#a%c', (af't", a%d 'fficac" of th' dru* roduct(, -. th' h"(icoch'#ical charact'ri(tic( of th' acti&' har#ac'utical i%*r'di'%t <API=,
1

1. th' h"(icoch'#ical charact'ri(tic( of th' do(a*' for#, 7. Th' rout' of ad#i%i(tratio%.

Th' ro 'rti'( of th' dru* a%d it( do(a*' for# ar' car'full" '%*i%''r'd a%d t'(t'd to roduc' a (ta>l' dru* roduct that u o% ad#i%i(tratio% ro&id'( th' d'(ir'd th'ra 'utic r'( o%(' i% th' ati'%t. Both th' har#aci(t a%d th' har#ac'utical (ci'%ti(t #u(t u%d'r(ta%d th'(' co# l'; r'latio%(hi ( to co# r'h'%d th' ro 'r u(' a%d d'&'lo #'%t of har#ac'utical(.

Th' dru* (u>(ta%c' a%d th' dru* for#ulatio% la" a% i# orta%t rol' o% th' a>(or tio% a%d di(tri>utio% of th' dru* to th' (it' of actio%. If th' co%c'%tratio% at th' (it' of actio% ';c''d( th' MEC, a har#acolo*ic r'( o%(' will r'(ult.

Th' actual do(i%* r'*i#'% <do(', do(a*' for#, do(i%* i%t'r&al= wa( car'full" d't'r#i%'d i% cli%ical trial( to ro&id' th' corr'ct dru* co%c'%tratio% at th' (it' of actio%.

Th' %atur' of th' dru* #ol'cul', rout' of d'li&'r", a%d th' for#ulatio% of th' do(a*' for# ca% d't'r#i%' wh'th'r a% ad#i%i(t'r'd dru* i( th'ra 'uticall" 'ff'cti&', to;ic, or ha( %o a ar'%t 'ff'ct at all. I(o rot'r'%ol cau('( a% i%cr'a(' i% h'art rat' wh'% *i&'% I? >ut ha( %o o>('r&a>l' 'ff'ct o% th' h'art wh'% *i&'% orall" at th' (a#' do(' l'&'l.

Bio har#ac'utic( i( th' (ci'%c' that ';a#i%'( th' r'latio%(hi of h"(icoch'#ical ro 'rti'( of th' dru*, th' do(a*' for# i% which th' dru* i( *i&'%, a%d th' rout' of ad#i%i(tratio% o% th' rat' a%d ';t'%t of ("(t'#ic a>(or tio% Bio har#ac'utic( i%&ol&'( factor( that i%flu'%c',
3

-. th' (ta>ilit" of th' dru* withi% th' dru* roduct, 1. th' r'l'a(' of th' dru* fro# th' dru* roduct, 7. th' rat' of di((olutio%@r'l'a(' of th' dru* at th' a>(or tio% (it', a%d 5. Th' ("(t'#ic a>(or tio% of th' dru*.

A>(or tio% Dru* r'l'a(' Dru* i% ("(t'#ic ti((u'( /a%d di((olutio% circulatio% Eli#i%atio% E;cr'tio% a%d Phar#acolo*ic@ M'ta>oli(# 'ff'ct

Dru* i%

Cli%ical

LADMER L A li>'ratio% A A a>(or tio%

4

D A di(tri>utio% M A #'ta>oli(# E A ';cr'tio% R A r'( o%('

Th' (tud" of >io har#ac'utic( i( >a('d o% fu%da#'%tal (ci'%tific ri%ci l'( a%d '; 'ri#'%tal #'thodolo*". Studi'( i% >io har#ac'utic( u(' >oth in&'itro a%d in&'i'o #'thod(. Th' #'thod( u('d #u(t >' a>l' to a(('(( th' i# act of th' h"(ical a%d ch'#ical ro 'rti'( of th' dru*, dru* (ta>ilit", a%d lar*'/(cal' roductio% of th' dru* a%d dru* roduct o% th' >iolo*ic 'rfor#a%c' of th' dru*.

Bio har#ac'utic( co%(id'r( th' ro 'rti'( of th' dru* a%d do(a*' for# i% a h"(iolo*ic '%&iro%#'%t, th' dru*B( i%t'%d'd th'ra 'utic u(', a%d th' rout' of ad#i%i(tratio%

BIOPHARMACEUTIC CO8SIDERATIO8S I8 DRU$ PRODUCT DESI$8

DRU$S ARE 8OT $E8ERALL0 $I?E8 AS A PURE CHEMICAL BUT !ORMULATED I8TO A !I8ISHED DOSA$E !ORM <DRU$ PRODUCT=. A !ORMULATED DRU$ PRODUCT USUALL0 I8CLUDES THE ACTI?E DRU$ SUBSTA8CE A8D SELECTED I8$REDIE8TS. A PRIMAR0 CO8CER8 I8 BIOPHARMACEUTICS IS THE BIOA?AILABILIT0 O! DRU$S. BIOA?AILABILIT0 RE!ERS TO THE MEASUREME8T O! THE RATE A8D ECTE8T O! DRU$ THAT REACHES THE S0STEMIC CIRCULATIO8. THE AIM O! BIOPHARMACEUTICS IS TO AD)UST THE DELI?ER0 O! DRU$
6

!ROM THE DRU$ PRODUCT I8 SUCH A MA88ER AS TO PRO?IDE OPTIMAL THERAPEUTIC ACTI?IT0 A8D SA!ET0 !OR THE PATIE8T.

BIOPHARMACEUTIC STUDIES ALLO. !OR THE RATIO8AL DESI$8 O! DRU$ PRODUCTS BASED O8, -. THE PH0SICOCHEMICAL PROPERTIES O! THE DRU$. 1. ROUTE O! DRU$ ADMI8ISTRATIO8 I8CLUDI8$ THE A8ATOMIC A8D PH0SIOLO$IC 8ATURE O! THE APPLICATIO8 SITE. 7. DESIRED PHARMACOD08AMIC E!!ECT <E$, IMMEDIATE OR PROLO8$ ACTI?IT0=. 5. TOCICOLO$IC PROPERTIES O! THE DRU$.
7

3. SA!ET0 O! ECCIPIE8TS. 6. E!!ECT O! ECCIPIE8TS A8D DOSA$E !ORM O8 DRU$ DELI?ER0.

EACH ROUTE O! DRU$ APPLICATIO8 PRESE8TS SPECIAL BIOPHARMACEUTIC CO8SIDERATIO8S I8 DRU$ PRODUCT DESI$8. E;a# l', -. Th' d'(i*% of a &a*i%al ta>l't for#ulatio% for th' tr'at#'%t of a fu%*al i%f'ctio% #u(t co%(id'r i%*r'di'%t( co# ati>l' with &a*i%al a%ato#" a%d h"(iolo*". 1. A% '"' #'dicatio% #a" r'Duir' ( 'cial >io har#ac'utic co%(id'ratio%( i%cludi%* a ro riat' H, i(oto%icit", (t'rilit", local irritatio% to th' cor%'a, drai%i%* >" t'ar(, a%d co%c'r% for ("(t'#ic a>(or tio%.
8

 THE RATE O! DRU$ RELEASE !ROM THE PRODUCT A8D THE RATE O! DRU$ ABSORPTIO8 ARE IMPORTA8T I8 DETERMI8I8$ THE DISTRIBUTIO8, O8SET, I8TE8SIT0, A8D DURATIO8 O! THE DRU$ ACTIO8. Bio har#ac'utic co%(id'ratio%( oft'% d't'r#i%' th' ulti#at' do(' a%d do(a*' for# of a dru* roduct.

Bio har#ac'utic( i( th' (tud" of th' r'latio% of th' h"(ical a%d ch'#ical ro 'rti'( of a dru* to it( >ioa&aila>ilit", har#aco+i%'tic(, a%d har#acod"%a#ic a%d to;icolo*ic 'ff'ct(.
<Bloc+ a%d Colli%(, 122-, Biopharmaceutics and Drug Deli'ery %ystems, i% Co# r'h'%(i&' Phar#ac" R'&i'w, Shar*'l 't al. 'd(, Li i%cott .illia#( 9 .il+i%(, 8'w 0or+=.

A dru* roduct i( th' fi%i(h'd do(a*' for# <'.*., ta>l't, ca (ul', (olutio%= that co%tai%( th' acti&' dru* i%*r'di'%t i% a((ociatio% with
9

%o%/dru* <u(uall" i%acti&'= i%*r'di'%t( <';ci i'%t(= that #a+' u th' &'hicl', or for#ulatio% #atri;. Th' hra(' dru* d'li&'r" ("(t'# i( oft'% u('d i%t'rcha%*'a>l" with th' t'r#( dru* roduct or do(a*' for#. How'&'r, a dru* d'li&'r" ("(t'# i( a #or' co# r'h'%(i&' co%c' t that i%clud'(, -. th' dru* for#ulatio% a%d th' d"%a#ic i%t'ractio%( a#o%* th' dru*, 1. it( for#ulatio% #atri;, 7. it( co%tai%'r, a%d 5. th' ati'%t. Bioa&aila>ilit" i( a #'a(ur'#'%t of th' rat' a%d ';t'%t <a#ou%t= of ("(t'#ic a>(or tio% of th' th'ra 'uticall" acti&' dru*. Phar#aco+i%'tic( i( th' (tud" of th' ti#' cour(' of dru* #o&'#'%t i% th' >od" duri%* a>(or tio%, di(tri>utio%, a%d 'li#i%atio% <';cr'tio% a%d >iotra%(for#atio%=. Phar#acod"%a#ic( i( th' (tud" of th' r'latio% of th' dru* co%c'%tratio% or a#ou%t at th'
10

(it' of actio% <r'c' tor= a%d it( har#acolo*ic r'( o%('.

RATE/LIMITI8$ !ACTORS I8 ORAL DRU$ ABSORPTIO8 A. Ph"(icoch'#ical Co%(id'ratio%( -. Stat' of Di( 'r(io% a%d !or#ulatio% !actor( a. Solu>ilit" >. Di((olutio% rat' c. R'l'a(' fro# di( 'r('d ("(t'# d. Ch'#ical (ta>ilit" 1. Tra%( ort Pro 'rti'( of th' Mol'cul'( a. Li o hilic@H"dro hilic Bala%c' E oft'% d't'r#i%'( 'r#'a>ilit" >. 4a E d't'r#i%'( ratio of char*'d to u%char*'d ( 'ci'( at a *i&'% H c. Mol'cular (iF' a%d (ha ' E d't'r#i%'( diffu(i&it"
11

B. Biolo*ical Co%(id'ratio%( -. Sto#ach a. H >. E# t"i%* rat' c. Surfac' t'%(io% d. E%F"#' 1. I%t'(ti%al Tract a. H >. Tra%(it ti#' a%d r'('r&' l'%*th c. Lu#'%al co%t'%t( d. Microcli#at' H '. Lu#'%al a%d >ru(h>ord'r #'ta>oli(# f. 8atur' of >io#'#>ra%' *. Muco(al c'll #'ta>oli(# h. Ba(olat'ral #'#>ra%' r'(trictio% to tra%( ort i. L"# hatic a>(or tio% j. P/*

12

THE BIOPHARMACEUTICS CLASSI!ICATIO8 SCHEME <BCS=

Cla(( Hi*h (olu>ilit" $ood 'r#'a>ilit" Cla(( 7 Hi*h (olu>ilit" Poor 'r#'a>ilit" Cla(( 1 Low (olu>ilit" $ood 'r#'a>ilit" Cla(( 5 Low (olu>ilit" Poor 'r#'a>ilit"

THE RULE O! 3
Thi( rul' of 3 (tat'( that oor a>(or tio%( or 'r#'atio%( ar' #or' li+'l" wh'%,

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1.Th'r' ar' #or' tha% 3 H/>o%d do%or( <'; r'(('d a( th' (u# of OH( a%d 8H(= 7.Th'r' ar' #or' tha% -2 H/>o%d acc' tor( <'; r'(('d a( th' (u# of 8( a%d O(= 5.Th' M. i( o&'r 322 3.Th' lo* artitio% co'ffici'%t i( o&'r 3 6.Co# ou%d cla(('( that ar' (u>(trat'( for >iolo*ical tra%( ort'r( ar' ';c' tio%( to th' rul'.

I8 ?ITRO/I8 ?I?O CORRELATIO8S

I% &itro/i% &i&o corr'latio%( <I?I?C= ar' >'co#i%* #or' i# orta%t >'cau(' >io'Dui&al'%c' of cha%*'( i% dru* roduct( ca% >' a ro&'d >" i% &itro t'(t( accordi%* to
14

th' SUPAC <(cal'/u a%d o(t/a cha%*'(= *uid'li%'(.

ro&al

I% th' futur' it ca% >' '; 'ct'd that *'%'ric dru* roduct( will >' a ro&'d (ol'l" o% th' >a(i( of i% &itro data if a% I?I?C ha( >''% '(ta>li(h'd. Th' >io'Dui&al'%c' (tudi'( will %ot alwa"( ha&' to >' co%duct'd. I% ?itro/i% ?i&o Corr'latio% E; 'ctatio%( for I##'diat' E R'l'a(' Product( >a('d o% th' Bio har#ac'utic( Cla((ificatio% Sch'#' Cla(( Solu>ilit" P'r#'a>ilit" I?I?C '; 'ctatio% Hi*h Hi*h I?I?C if di((olutio% rat' i( (low'r tha% *a(tric '# t"i%* rat', oth'rwi(' li#it'd or %o corr'latio%. I?I?C

Low

Hi*h
15

'; 'ct'd if i% &itro di((olutio% rat' i( (i#ilar to i% &i&o di((olutio% rat', u%l'(( do(' i( &'r" hi*h. 7 Hi*h Low A>(or tio% < 'r#'a>ilit"= i( rat' E d't'r/ #i%i%* a%d li#it'd or %o I?I?C with di((olutio% rat'. Li#it'd or %o I?I?C '; 'ct'd.

Low

Low

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$ASTROI8TESTI8AL DISEASE A8D DOSA$E !ORM PER!ORMA8CE

Dru* a>(or tio% fro# th' *a(troi%t'(ti%al tract i( i%flu'%c'd >" factor(, -. *a(tric a%d i%t'(ti%al #otilit" 1. h"(icoch'#ical ro 'rti'( of th' '%&iro%#'%t i% th' (#all i%t'(ti%' 7. Surfac' ar'a a&aila>l' for a>(or tio%.

$a(troi%t'(ti%al di('a('(, ("(t'#ic di('a('( with i%t'(ti%al i%&ol&'#'%t, a%d th' co%('Du'%c'( of *a(troi%t'(ti%al (ur*'r" #a" #odif" a%" or all of th' factor( #'%tio%'d a>o&', Su>('Du'%tl", cha%*'( i% th' th'ra 'utic 'ff'ct( of dru*( ad#i%i(t'r'd >" th' oral rout' #a" occur.
17

 Bioa&aila>ilit" ca% d'&iat' *r'atl" fro# that i% h'alth" (u>j'ct(. Cli%icia%( a%d har#aci(t( (hould >' awar' that i% ati'%t( with *a(troi%t'(ti%al di('a('( th' o((i>ilit" of alt'r'd >ioa&aila>ilit" ';i(t(, a%d a%tici at' a%" #o%itori%* of, or alt'ratio% i%, th'ra " that #a" ha&' to >' #ad'.

I8TESTI8AL MALABSORPTIO8 A8D MALDI$ESTIO8

Mala>(or tio% Mala>(or tio% i( d'fi%'d a( i# air'd a>(or tio% of %utri'%t(, occurri%* 'ith'r wh'% th'r' i(, -. A d'f'ct i% #'#>ra%' tra%( ort ("(t'#( of th' (#all i%t'(ti%al ' ith'liu#, without #or holo*ical cha%*'( < ri#ar" #ala>(or tio%=
18

1. D'f'ct( i% th' ' ith'lial a>(or ti&' (urfac', with co%co#ita%t #or holo*ical cha%*'( of th' #uco(a <('co%dar" #ala>(or tio%=.

Th' #ajor atho h"(iolo*ical #'cha%i(#( i% #ala>(or tio% ar' a( follow(, -. D'f'ct( of th' lu#i%al ha(' of di*'(tio% 1. D'f'ct( of th' #uco(al ha(' of t'r#i%al di*'(tio% a%d a>(or tio% 7. D'f'ct( of th' tra%( ort ha('.

!at Mala>(or tio% !at #ala>(or tio% #a" aff'ct a>(or tio% of li o hilic dru* for#ulatio%(. Th' #'cha%i(#( of fat di*'(tio% a%d a>(or tio% ar',
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-. Di'tar" tri*l"c'rid'( ar' d'*rad'd >" a%cr'atic li a(' to #o%o*l"c'rid' a%d fatt" acid(. 1. Bil' (alt( i% th' j'ju%al lu#'% ar' r'( o%(i>l' for #ic'll' for#atio% a%d (u>('Du'%t (olu>iliFatio% of #o%o*l"c'rid'( a%d fatt" acid(, allowi%* th'# to '%'trat' th' i%t'(ti%al #uco(a. 7. Tri*l"c'rid'( ar' r'("%th'(iF'd i% th' #uco(a a%d, i% th' for# of ch"lo#icro%(, ar' tra%( ort'd fir(t to th' i%t'(ti%al l"# hatic( a%d (u>('Du'%tl" i%to th' *'%'ral circulatio%.

So#' of th' ot'%tial cau('( of fat #ala>(or tio% St'atorrh'a E (tool fat G H *@da" E l'ad( to '%t'ral lo(( of di'tar" fat, li id/(olu>l' &ita#i%(, a%d calciu#, a( w'll a( to a% i%cr'a('d o;alat' a>(or tio% I'%t'ricJ h" 'ro;aluria.
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 Di(tur>a%c'( of >il' acid #'ta>oli(# #a" al(o cau(' (t'atorrh'a a%d #ala>(or tio%, >" i# air#'%t of th' #ic'llar ha(' of fat di*'(tio% i% th' (#all/i%t'(ti%al lu#'%. A% ';c'(( '%t'ral lo(( of >il' acid( ca% r'(ult i% wat'r" diarrh'a owi%* to th' i# air#'%t of wat'r r'a>(or tio% i% th' colo% >" >il' acid(. S#all i%t'(ti%al >act'rial o&'r*rowth i( a co%('Du'%t of #or holo*ical cha%*'( of th' i%t'(ti%'

THE BIOPHARMACEUTICS CLASSI!ICATIO8 SCHEME <BCS=

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Cla(( Hi*h (olu>ilit" $ood 'r#'a>ilit" Cla(( 7 Hi*h (olu>ilit" Poor 'r#'a>ilit"

Cla(( 1 Low (olu>ilit" $ood 'r#'a>ilit" Cla(( 5 Low (olu>ilit" Poor 'r#'a>ilit"

THE RULE O! 3
Thi( rul' of 3 (tat'( that oor a>(or tio%( or 'r#'atio%( ar' #or' li+'l" wh'%, H.Th'r' ar' #or' tha% 3 H/>o%d do%or( <'; r'(('d a( th' (u# of OH( a%d 8H(= K.Th'r' ar' #or' tha% -2 H/>o%d acc' tor( <'; r'(('d a( th' (u# of 8( a%d O(=

22

:.Th' M. i( o&'r 322 -2. Th' lo* artitio% co'ffici'%t i( o&'r 3

--. Co# ou%d cla(('( that ar' (u>(trat'( for >iolo*ical tra%( ort'r( ar' ';c' tio%( to th' rul'.

I8 ?ITRO/I8 ?I?O CORRELATIO8S

I% &itro/i% &i&o corr'latio%( <I?I?C= ar' >'co#i%* #or' i# orta%t >'cau(' >io'Dui&al'%c' of cha%*'( i% dru* roduct( ca% >' a ro&'d >" i% &itro t'(t( accordi%* to th' SUPAC <(cal'/u a%d o(t/a ro&al cha%*'(= *uid'li%'(. I% th' futur' it ca% >' '; 'ct'd that *'%'ric dru* roduct( will >' a ro&'d (ol'l" o% th' >a(i( of i% &itro data if a% I?I?C ha( >''%
23

'(ta>li(h'd. Th' >io'Dui&al'%c' (tudi'( will %ot alwa"( ha&' to >' co%duct'd. I% ?itro/i% ?i&o Corr'latio% E; 'ctatio%( for I##'diat' E R'l'a(' Product( >a('d o% th' Bio har#ac'utic( Cla((ificatio% Sch'#' Cla(( Solu>ilit" P'r#'a>ilit" I?I?C '; 'ctatio% Hi*h Hi*h I?I?C if di((olutio% rat' i( (low'r tha% *a(tric '# t"i%* rat', oth'rwi(' li#it'd or %o corr'latio%. I?I?C '; 'ct'd if i% &itro di((olutio% rat' i( (i#ilar to i% &i&o di((olutio% rat', u%l'((

Low

Hi*h

24

do(' i( &'r" hi*h. 7 Hi*h Low A>(or tio% < 'r#'a>ilit"= i( rat' E d't'r/ #i%i%* a%d li#it'd or %o I?I?C with di((olutio% rat'. Li#it'd or %o I?I?C '; 'ct'd.

Low

Low

PERMEABILIT0
Pr'dictio% of 'r#'a>ilit" i% th' tra%(/ c'llular rout' ha( >''% #od'l'd >a('d o% h"(icoch'#ical ro 'rti'( of co# ou%d(, a%d th'(' a roach'( ha&' #'t with (o#' (ucc'((.
25

 How'&'r, th' r'('%c' of acti&' a%d a((i&' carri'r/#'diat'd tra%( ort athwa"( i% th' i%t'(ti%al ' ith'liu# ha&' r'clud'd co# ou%d ('l'ctio% >a('d o% h"(icoch'#ical ro 'rti'( alo%'. Th' tra%(/c'llular athwa" i( th' #o(t (i*%ifica%t athwa" du' to th' c'll #'#>ra%' (urfac' ar'a #a+'( u #or' tha% ::L of th' total (urfac' ar'a of th' i%t'(ti%'. P'r#'a>ilit" athwa"( for dru*( acro(( ' ith'lial c'll(.

26

 CASE STUD0 !OR PERMEABILIT0

E%doth'li% <ET= i( a ot'%t &a(oco%(trictor ' tid' that ha( >''% i# licat'd i% th' atho h"(iolo*" of di('a('. D'&'lo #'%t of %o%/ ' tid' '%doth'li% r'c' tor a%ta*o%i(t ha( >''% u%d'rta+'% to all'&iat' th' atho h"(iolo*ical 'ff'ct( a((ociat'd with '%doth'li% i%t'ractio% at it( r'c' tor(. Pot'%t a%d ('l'cti&' %o%/ ' tid' '%doth'li% r'c' tor a%ta*o%i(t( ha&' >''% d'&'lo 'd a( (how% >'low.

27

 Th' >ioa&aila>ilit" of SB 12:6H2 wa( low wh'% ad#i%i(t'r'd orall" i% a%i#al(. Th' i%t'(ti%al 'r#'a>ilit" of SB 12:6H2 wa( l'(( tha% 2.2- c#@h i% >oth Caco/1 c'll( a%d ra>>it i%t'(ti%al ti((u'(. Th' cutoff &alu' of i%t'(ti%al 'r#'a>ilit" for ('l'ctio% of ot'%tial dru* ca%didat'( i( 2.2- c#@h. It wa( (u**'(t'd that SB 12:6H2 wa( tra%( ort'd acro(( th' i%t'(ti%al ' ith'liu# >" a a((i&' roc'((. Th' li#it'd 'r#'a>ilit" a%d oral >ioa&aila>ilit" of th' dru* #a" >' du' to th' dicar>o;"lic acid( i% th' (tructur' < 4a M 3.3=. Co# ari%* th' SB 12:6H2 with SB 121::5, th' #o%ocar>o;"lic acid a%alo*u' a%d a% i%acti&' dru*, th' 'r#'a>ilit" of SB 121::5 wa( M 2.1 c#@h i% ra>>it i%t'(ti%'. P'r#'a>ilit" &alu' of 2.21 c#@h i( (i#ilar to a dru* ha&i%* >ioa&aila>ilit" *r'at'r tha% :2L. Thi( (u ort( th' h" oth'(i( that th' r'('%c' of two char*'d *rou ( i# 'd'( a((a*' acro(( th' *ut wall. A hi*hl" ot'%t #o%ocar>o;"lic acid a%alo*u', SB 1-H151, tra&'r('( th' i%t'(ti%al ' ith'liu# i% M t'%fold a( th' >athi%* (olutio% H i( r'duc'd fro# K to 3.3.

28

 Th' d'&'lo #'%t of dru*( to r'&'%t thro#>o(i( i( (how% >" $PII>@IIIa a%ta*o%i(t( a( (how% >'low.

S4! -2H162 i( a c"clic ' tid' that i( a ot'%t $PII>@IIIa r'c' tor a%ta*o%i(t. Thi( co# ou%d ha( low 'r#'a>ilit" i% ra>>it il'u# < 'r#'a>ilit" N 2.227 c#@h= a%d al(o low >ioa&aila>ilit" <N 3L= i% a%i#al(. SB 12H55K i( a %o%/ ' tid' #i#'tic with *ood ot'%c" for a%ta*o%i(# at th' $PII>@IIIa r'c' tor, >ut th' 'r#'a>ilit" i( l'(( tha% 2.22- c#@h i% ra>>it il'u#. At h"(iolo*ical H, thi( co# ou%d will >' char*'d at th' >oth car>o;"lic acid a%d th' a#i%' fu%ctio%(. Th' 'r#'a>ilit" &alu' of SB 12K577 i( 2.21 c#@h a%d 12/ fold *r'at'r tha% that of SB 12H55K, wh'r'a( th' 'r#'a>ilit" &alu' of SB 12:H3- i( 2.25 c#@h a%d 1/fold *r'at'r tha% SB 12K577. Th'(' r'(ult( (u**'(t that th' #ajor co%tri>uti%* factor to th' li#it'd 'r#'a>ilit" of SB 12H5KK i( th' char*'d
29

a#i%o *rou . Co# ou%d( with l'(( >a(ic a#i%o/t'r#i%al fu%ctio%( w'r' ("%th'(iF'd, i.'., SB 117153 a%d SB 117157, a( (how% >'low.

SB 117153 ha( low 'r#'a>ilit" <N 2.2- c#@h= i% ra>>it i%t'(ti%al ti((u'( du' to a Fwitt'r/io%ic co# ou%d. SB 117157 i( a #'th"l '(t'r of SB 117153 a%d ha( a hi*h 'r#'a>ilit" i% th' >a(olat'ral <>lood=/to/lu#'%al dir'ctio% with 'r#'a>ilit" &alu' of 2.11 c#@h. How'&'r, th' lu#'%/to/>lood 'r#'a>ilit" i( l'(( tha% 2.2- c#@h i% ra>>it i%t'(ti%'. Th'(' r'(ult( (u**'(t that i% #odif"i%* th' (tructur' to '%ha%c' 'r#'a>ilit", th' co# ou%d ha( >'co#' a (u>(trat' for a% acti&' 'fflu; #'cha%i(#. Th' r'('%c' of a% acti&' 'fflu; roc'(( for SB 117157 could li#it i%t'(ti%al a>(or tio% a%d al(o co%tri>ut' to oth'r i((u'(, (uch a( dru*/dru* i%t'ractio%(, hi*h &aria>ilit" i% a>(or tio%, a%d food 'ff'ct(.

30

SOLUBILIT0
AS A LIMITI8$ !ACTOR TO DRU$ ABSORPTIO8
Mo(t dru* (u>(ta%c'( ca% 'r#'at' th' i%t'(ti%al *ut #'#>ra%' >" tra%(c'llular a((i&' diffu(io%. Thi( roc'(( i( d't'r#i%'d >" h"(icoch'#ical ro 'rti'( of th' dru*( a%d >" th' ro 'rti'( of th' i%t'(ti%al c'll(. !RACTIO8 DOSE ABSORBED O! POORL0 SOLUBLE DRU$S Th' Bio har#ac'utic( Cla((ificatio% S"(t'# <BCS= co#>i%'( h"(icoch'#ical ro 'rti'( of co# ou%d( a%d h"(iolo*ical factor( to r'dict th' fractio% do(' a>(or>'d fro# $IT. Th' 'r#'a>ilit" of a *i&'% dru* d't'r#i%'( th' u li#it of it( ';t'%t of a>(or tio%. 'r

Th' i%t'ractio% of th' h"(iolo*ical '%&iro%#'%t with h"(icoch'#ical charact'ri(tic( of th' dru* ca% ha&' a% i%flu'%c' o% th' a&aila>ilit" of th' dru* at th' a>(or tio% (it'. Th' -. 1. 7. 5. 3. 6. H. h"(iolo*ical '%&iro%#'%t, *a(tric H *a(tric '# t"i%* ti#' i%t'(ti%al H tra%(it ti#' *a(troi%t'(ti%al #otilit" lu#i%al #'ta>oli(# '%do*'%ou( (u>(ta%c'( <'.*., >il' (alt(=
31

K. ';o*'%ou( (u>(ta%c'( <'.*., food a%d %utri'%t(=. Th' h"(icoch'#ical ro 'rti'( of th' dru*, -. 4a 1. (olu>ilit" i% th' *ut lu#'% 7. di((olutio% rat' 5. aDu'ou( diffu(i&it" 3. artitio% co'ffici'%t 6. Ch'#ical a%d '%F"#atic (ta>ilit" i% th' i%t'(ti%'. Th' ';t'%t of oral a>(or tio% #a" >' '(ti#at'd >" th' !ic+B( fir(t law, )w A Pw. Cw A <dM@dt=<-@A= P'ff <Ci% E Cout= Oi% A /////////////////////////// Cout <1 r L=

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