Effect of Gongjindan, a Traditional Korean Polyherbal Formula, on the Pharmacokinetics Profiles of Donepezil in Male SDRats (2) - Single Oral Combination Treatment of Donepezil 10mg/kg with Gongjindan 100mg/kg, 1.5hr-intervals with 7-day Repeated Treatmen

․ 접수 : 2 0 1 3 년 3 월 1 6 일 ․ 수정접수 : 2 0 1 3 년 8 월 3 일 ․ 채택 : 2 0 1 3 년 8 월 6 일

*공동교신저자 : 이영준,대구한의대학교 한의과대학 예방의학교실,경북 경산시 한의대로 1 ,7 1 2 -7 1 5 전화 : 0 5 3 -8 1 9 -1 2 9 6 ,팩스 : 0 5 3 -8 1 9 -1 5 7 6 ,전자우편 : gk s xnt k @d hu. a c . kr

구세광,대구한의대학교 한의과대학 해부학교실,경북 경산시 한의대로 1 ,7 1 2 -7 1 5 전화 : 0 5 3 -8 1 9 -1 5 4 9 ,팩스 : 0 5 3 -8 1 9 -1 5 7 6 ,전자우편 : gu c c i 2 0 0 @ha nma i l . ne t

Ko r .J .Or i e n t a lPr e v e n t i v eMe d i c a lSo c i e t y2 0 1 3 ；1 7 ( 2 ) ：1 3 9 - 1 5 5

Effect of Gongjindan, a Traditional Korean Polyherbal Formula, on the Pharmacokinetics Profiles of Donepezil in Male SDRats (2)

― Single Oral Combination Treatment of Donepezil 10mg/kg with Gongjindan 100mg/kg, 1.5hr-intervals with 7-day Repeated Treatment ―

Oh Dae Kwon,

Dae-Kyoo Chung,

Soo Jin Park,

Young Joon Lee

& Sae Kwang Ku

1)

Depar t mentofNeur ol ogy ,Cat hol i cUni v er s i t yofDaeguSc hoolofMedi c i ne,Daegu

2)

Depar t mentofNeur ops y c hi at r y ,Col l egeofKor eanMedi c i ne,DaeguHaanyUni v er s i t y ,Gy eongs an

3)

Depar t mentofAnat omyandHi s t ol ogy ,Col l egeofKor eanMedi c i ne,DaeguHaanyUni v er s i t y ,Gy eongs an

4)

Depar t mentofPr ev ent i v eMedi c i ne,Col l egeofKor eanMedi c i ne,DaeguHaanyUni v er s i t y ,Gy eongs an

5)

TheMedi c alRes ear c hc ent erf orGl obal i z at i onofHer balFor mul at i on,DaeguHaanyUni v er s i t y ,Gy eongs an

Abstract

Purpose : Thi ss t ud y wa sa i m t oe va l ua t ee f f e c t so fp ha r ma c o d yna mi c sa nd t o xi c i t y i n c o mb i na t i o n t he r a p yo fd o ne p e z i lwi t hGo ngj i nd a n. Thee f f e c t so fGo ngj i nd a nc o -a d mi ni s t r a t i o no nt hep h a r ma c o k i ne t i c s ( PK)o fd o n e p e z i lwe r eo b s e r ve da f t e rs i n gl ea n d7 -d a yr e p e a t e do r a lc o -a d mi n i s t r a t i o nwi t h1 . 5 h r -i nt e r va l s , t oe va l ua t es yne r gi cpha r mac o dyna mi c sa ndr e duc et o xi c i t yo fc o mbi na t i o nt he r a pyo fdo ne pe z i lwi t h Go ngj i nd a n.

Materials and Methods : Af t e r1 0 mg/ k go fd o ne p e z i lt r e a t me nt ,Go ngj i nd a n1 0 0 mg/ kgwa sa d mi ni s t e r e d wi t h1 . 5 hr -i nt e r va l s .Th ep l a s mawe r ec o l l e c t e da t3 0 mi nb e f o r ea d mi ni s t r a t i o n,3 0 mi n,1 ,2 ,3 ,4 ,6 ,8a nd 2 4 hr sa f t e re ndo ff i r s ta nd l a s t7 t h d o ne p e z i lt r e a t me nt ,a nd p l a s mac o nc e nt r a t i o nso fd o ne p e z i lwe r e a na l yz e dus i ngLC-MS/ MSme t h o d s .

Results : Gongj i nd a n ma r ke d l y i nhi bi t e d t h e a bs o r p t i o n o fd o ne p e z i l r e ga r d l e s s o fs a mp l et i me ,f r o m 3 0 mi nt o8 hr sa f t e re ndo ff i r s t1 . 5 hr -i nt e r va lc o -a d mi ni s t r a t i o na sc o mp a r e dwi t hd o ne p e z i ls i ngl et r e a t e d r a t s .Es pe c i a l l y t hea bs o r p t i o n o fdo ne p e z i l wa ss i gni f i c a nt l y de c r e a s e d a t2 ,4 ,6a nd 8 hr sa f t e rc o - a d mi ni s t r a t i o na sc o mp a r e dwi t hd o ne p e z i l s i ngl et r e a t e dr a t s .Ac c o r d i ngl y,t heCma x( -2 6 . 2 3 6 %) ,AUC

( -2 6 . 0 2 %)a ndAUC

( -2 5 . 9 0 %) o fdo ne pe z i li n1 . 5 hr -i nt e r va lc o -a dmi ni s t e r e dr a t swe r edr a ma t i c a l l y

d e c r e a s e da sc o mp a r e dwi t hd o ne p e z i l s i ngl et r e a t e dr a t s ,r e s p e c t i ve l y.Ho we ve r ,nome a ni ngf ulc ha nge so n t hep l a s mado ne p e z i lc o nc e nt r a t i o nsa ndp ha r ma c o ki ne t i cp a r a me t e r swe r ed e t e c t e da f t e re ndo fl a s t7 t h 1 . 5 h r -i nt e r va lc o -a d mi ni s t r a t i o na sc o mp a r e dwi t hd o ne p e z i ls i ngl et r e a t e dr a t s ,e xc e p tf o rno n-s i gni f i c a nt s l i ghti nc r e a s e so fTma x( 1 6 . 6 7 %)d e t e c t e d i n c o -a d mi ni s t e r e d r a t sa sc o mp a r e d wi t h d o ne p e z i ls i ngl e t r e a t e dr a t s .

Conclusion : Thesef i ndi ngsa r ec o ns i de r e da sdi r e c te vi de nc e st ha tGo ngj i nda na l s ode c r e a s e do r a l bi o a va i l a bi l i t y o fdo ne p e z i la si nhi bi t e dt hea bs o r pt i o ns ,whe nt he y we r ec o -a dmi ni s t e r e dwi t h1 . 5 hr - i nt e r va l s ,b utt he yma yb ea d a p t e da f t e r7d a ysc o nt i nuo usr e p e a t e d1 . 5 hr -i nt e r va lc o -a d mi ni s t r a t i o n.

Key wor ds：Go ngj i nda n,Pha r ma c o ki ne t i c s ,Dr ug-dr ug i nt e r a c t i o ns ,Ra t ,Do ne pe z i l ,Re pe a t or aldos e

1. Introduction

Do ne pe z i l( Ar i c e pt

)i sac e nt r a l l ya c t i ng r e ve r s i bl ea c e t yl c hol i ne s t e r a s ei nhi bi t or ,a nd ma i nt he r a p e ut i cus ei si nt hepa l l i a t i vet r e a t - me nto fmi l dt omo d e r a t eAl z he i me r ’ sd i s e a s e

. Do ne pe z i li si ndi c a t e df o rs ympt o ma t i ct r e a - t me ntofpa t i e nt swi t hmi l d,mode r a t ea nd s e ve r ede me nt i aoft heAl z he i me r ’ st ype

. Do ne pe z i lha sbe e nt e s t e di no t he rc o gni t i ve di s o r de r si nc l udi ngLe wybo dyde me nt i a

a nd va s c ul a rde me nt i a

.Do ne pe z i lha sa l s obe e n f o undt oi mp r o ves l e e pa p ne ai nAl z he i me r ’ s p a t i e nt s

,a ndr e c e nt l yt hee vi d e nc et ha tdo ne - pe z i lc ani mpr oves pe e c hi nc hi l dr e nwi t h a ut i s m wa sa l s os ugge s t e d

.Ho we ve r ,i ta l s o s ho we ds e ve r et o xi c i t yi np r e c l i ni c a ls t udi e s , 5 0 % l e t ha ldo s e( LD

)i nr o de nt sa r el o c a t e d be t we e n3 0 ～4 0 mg/ kg,a ndNoObs e r ve dEf f e c t Le ve l ( NOEL)o f1 3we e ksr e p e a td o s et o xi c i t y t e s ti nr a ta n dd o gi s1 mg/ kg/ d a y,r e s p e c t i ve l y

a ndunde s i r a bl es i dee f f e c t si nc l i ni c a lus e

. Co mmo n s i dee f f e c t si nc l udega s t r o i nt e s t i na l ups e t ;i nc l udebr a dyc a r di a,na us e a ,di a r r he a ,

anor e xi a,abdomi na lpa i n,vi vi ddr e a ms ,a nd ma ni a

.

Asr e s ul t sofc ombi nat i ont he r api e swi t h

o t h e rd r ugst oi mp r o vet h es i d ee f f e c t so fd o n e -

pe z i lort oa c hi e ves yne r gi ce f f e c t s ,var i ous

dr ug-dr ugi nt e r a c t i o nso fd o ne pe z i lha vebe e n

e va l ua t e d;Al t ho ugh,pha r ma c o ki ne t i cs t udi e s

s ho we dnos i gni f i c a nte f f e c t so fdone pe z i lo n

t hepha r ma c oki ne t i cpr of i l e sofc i me t i di ne

,

c o mbi na t i onsc o nt a i ni nga nyo ft hef ol l o wi ng

me di c a t i o ns ,de pe ndi ngo nt hea mo untpr e s e nt ,

mayal soi nt er actwi t hant i chol i ner gi cs-

c ho l i ne s t e r a s ei nhi bi t o r ss uc ha sd o ne p e z i lha ve

t hepo t e nt i a lt oi nt e r f e r ewi t ht hea c t i vi t yo f

t h e s eme d i c a t i o n s ,n o n s t e r o i d a la n t i -i n f l a mma t o r y

d r ugs( NSAI Ds )-d o ne p e z i lma yi nc r e a s ega s t r i c

ac i ds e c r e t i onduet oi nc r e as e dc hol i ne r gi c

a c t i vi t yp a t i e nt ss ho ul dbemo ni t o r e df o rs ym-

pt omsofact i veoroc cul tgast r oi nt e st i nal

bl e e di nga ndc a r ba ma z e pi ne ,de xa me t ha s one ,

phe noba r bi t al ,phe nyt o i no rr i f ampi n-The y

mayi nduc et hei soenzyme sCYP2D6and

CYP3 A4 ,t husi n c r e a s i ngt h er a t eo fe l i mi na t i o n

ofdo ne pe z i l

.I na ddi t i o nc o nc ur r e ntus eof

c ho l i ne r gi ca go ni s t sl i ke ,be t ha ne c ho lo rne ur o -

mu s c u l a rb l o c ki nga ge nt sme t a bo l i z e dbyp l a s ma

c ho l i ne s t e r a s el i kes uc c i nyl c ho l i nea ndmi va - c ur i um wi t hd o ne pe z i lma ybee xp e c t e dwi t h as yne r gi s t i ce f f e c t

.Ke t o c o na z o l ea l s oc a nbe i nf l ue nc e do nt hep ha r ma c o ki ne t i c sa ndp ha r - ma c o dyna mi c so fdo ne p e z i lt hr o ughi nhi bi t i o n o ft heme t a bo l i s m o fdo ne p e z i l

.I nt e r a c t i o ns wi t hhe r ba lp r o duc t sha veno tbe e ne s t a bl i s he d e xc e ptf o rs o mer e s t r i c t e ds i ngl ehe r be xt r a c t s o rna t ur a lc o mp o und s ;Gi n k gob i l o b ae xt r a c t s

, di goxi n

,t he o phyl l i ne

,orwa r f ar i n

,di d noti nf l ue nc e dont hephar mac oki ne t i c sof do ne p e z i l .

Go ngj i nda n,at r a di t i o na lKo r e a npo l yhe r ba l f o r mul ai so neo ft hemo s tf a mo ust o ni ca ge nt s , a ndc o ns i s t e do f4he r bsi nc l udi ngAnge l i c a e gi ga sr a d i x,Gi ns e ngs t e a me dr e d ,Co r n if r uc t us a ndRe h ma nni a e r a di xp r e pa r a t a ,a nd2a ni ma l r e s o ur c e s-a nt l e ra ndmus k.The s e6a ge nt s we r epl a s t e r e dus i ngho ne y,a ndc o a t e dby gol dpl a t e s .Thehypol i pi de mi ca ndi mmune s t i mul a t o r ye f f e c t so fGo ngj i nd a na r er e l a t i ve l y wel ldocument ed

wi t h ant i -oxi dat i ve e f f e c t s

,a nt i -gl i o s i se f f e c t so nmi d d l ec e r e b r a l ar t er yoc cl usi onr at s

andant i -dement i a e f f e c t s

.I na dd i t i o n,s i ngl eo r a ldo s et o xi - c i t y

a ndmi c r o nuc l e ust e s t

ofGongj i nda n i t s e l fwe r ea l r e a dyr e p o r t e d.

I n t hep r e vi o uss t udy

,c o -a dmi ni s t r a t i o n ofGongj i ndanwi t hdone pe z i lwi t hi n5mi n s h o we dma r k e dd e c r e a s e so fd o n e p e z i la b s o r p t i o n a ndc o ns e que nt l y,r e duc e dt heo r a lbi o a va i l - a bi l i t yo fdone pe z i l ,t he r e f or e ,t hee f f e c t sof Go ngj i nda nc o -a dmi ni s t r a t i o no nt hep ha r ma -

c oki ne t i c sofdone pe z i lwe r eobs e r ve daf t e r s i ngl ea nd7 -da yr e pe a t e dor a lc o -admi ni - s t r a t i o nwi t h1 . 5 h r -i n t e r v a l s( r e a s o n a b l ei nt e r va l s c o ns i de r i ngt heTma xa f t e rdo ne pe z i ls i ngl e o r a la dmi ni s t r a t i o n de t e c t e d i n t hepr e vi o us

s t udy

)a sap r o c e s so ft hec o mp r e he ns i ve a ndi nt e gr a t i veme d i c i ne ,c o mbi na t i o nt he r a p y ofdonepez i lwi t h Gongj i ndan t o achi e ve s yne r gi cp h a r ma c o d yna mi c sa ndr e d uc et o xi c i t y i nt hep r e s e n ts t ud y.Af t e r1 0 mg/ k go fd o n e p e z i l t r e a t me nt ,Go ngj i nda n1 0 0 mg/ kgwa sa dmi ni s t e r e d wi t h1 . 5 hr -i n t e r va l s .Thep l a s mawe r ec o l l e c t e d a t3 0 mi nbe f o r ea dmi ni s t r a t i o n,3 0 mi n,1 ,2 ,3 , 4 ,6 ,8a nd2 4 hr sa f t e re ndo ff i r s ta ndl a s t7 t h do ne p e z i lt r e a t me nt ,a ndp l a s mac o nc e nt r a t i o ns o fdo ne p e z i lwe r ea na l yz e dus i ngLC-MS/ MS me t ho ds .PK pa r a me t e r so fd o ne pe z i l ( Tma x, Cma x,AUC,t

a ndMRT

)we r ea na l ys i sa s c o mpa r e dwi t h do ne p e z i ls i ngl ea d mi ni s t e r e d r a t s .

2. Materials &Methods 2 . 1 .An i ma l sa n dh u s b a n d r y

To t a lt e nma l eSpr a gue -Da wl e y( SD) r a t s( 6 - wkol duponr e c e i pt ,SLC,J a pa n)we r eus e d a f t e ra c c l i ma t i z a t i o nf o r9da ys .Ani ma l swe r e al l oc at e df i vepe rpol yc ar bonat ec agei na t e mpe r a t ur e( 2 0 -2 5 ℃)a ndhumi di t y( 4 0 -4 5 %) c o nt r o l l e dr o o m.Li ght:da r kc yc l ewa s1 2 hr:

1 2 hra ndf e e d( Samya ng,Kor e a )a ndwat e r we r es up p l i e df r e et oa c c e s s .Al la ni ma l swe r e ma r ke dby pi c r i ca c i d,a ndo ve r ni ghtf a s t e d ( a bo ut1 8hr s ;wa t e rwa sno tr e s t r i c t e d)be f o r e f i r s ta ndl a s tt r e a t me nt ,a ndf ur t he rf a s t e d dur i ng3hr sa f t e re ndo ft r e a t me nt .

2 . 2 .Te s ta r t i c l e sa n df o r mu l a t i o n

Gongj i ndan,pr e par e da ndpur c has ef r om

Da e guOr i e nt a lHo s p i t a l s ,Da e guHa a nyUni -

Ta b l e1 .Co mp o s i t i o no fGo n g j i n d a nUs e di nTh i sSt u d y

He r bs Sc i e nt i f i cNa me s Amo unt s( g/ 1p i l l ) Ant l e r( Co r nusc e r vip a r vum) Ce r v use l a ph usLi nne 0 . 6 8 3 Ange l i c a egi ga nt i sr a di x An ge l i c agi ga sNa ka i 0 . 6 8 3 Gi ns e ngs t e a me dr e d Pa na xgi ns e ngCA Me y. 0 . 6 8 3 Co r nif r uc t us Co r n uso f f i c i na l i sSi e b.EtZuc c 0 . 6 8 3 Re hma nni a er a d i xpr e p a r a t a Re h ma n ni agl ut i no s a( Ga e r t ne r )Li bo s c hi t z 0 . 6 8 3 Mus k Mo s c h usmos c h i f e r usLi nne 0 . 1 2 2 Ho ne y Api si ndi c aRa d o s z ko ws ki 2 . 5 0 6

Go l dp l a t e 0 . 0 0 6

To t a l 8t yp e s 6 . 0 5 0

Go ngj i nd a n us e d i n t hi s s t udy wa s p ur c ha s e d f r o m Da e gu Or i e nt a lHo s pi t a lo f Da e gu Ha nny Uni ve r s i t y( Da e gu,Ko r e a )

ve r s i t y( Ta bl e1 ;Da e gu,Ko r e a )a ndd o ne pe z i l ( J e i lPha r m. ,Co . ,Lt d,Yo ungi n,Ko r e a )wa s us e da sc o nt r o ld r uga sl i s t e df o l l o ws .Do ne p e z i l a ndGo ngj i nda nwe r es t o r e di nar e f r i ge r a t o ra t 4℃ t opr ot e c tf r om l i ghtandde ge ner at i on unt i lus e .Bot hdr ugsa r ewe l ls us pe nde dor d i s s o l ve d( up t o2 0mg/ mls us p e ns i o nsi nGo n g- j i nda na ndup t o2 mg/ mls o l ut i o nsi ndo ne p e z i l ) i ndi s t i l l e dwa t e ra sve hi c l e ,r e s pe c t i ve l y.

2 . 3 .Gr o u p i n g sa n da d mi n i s t r a t i on

Fi ver a t sp e rgr o up( t wogr o up s )we r eus e d i n t hi ss t ud y a sf o l l o ws .Thed o s e so ft e s t ma t e r i a l swe r es e l e c t e dba s e do nt he i r t o xi c i t y a ndp ha r ma c o d yna mi c s-1 0 mg/ kgo fd o ne p e z i l wi t h1 0 0 mg/ kgo fGo ngj i nda n.Af t e r1 0 mg/ kg o fdo ne pe z i lt r e a t me nt ,Go ngj i nda n1 0 0 mg/ kg wasadmi ni st er e dwi t h1. 5hr -i nt er val s.I n d o ne p e z i ls i ngl et r e a t e dr a t s ,1 0 mg/ k go fd o ne - p e z i lwa so r a l l ya dmi ni s t e r e da nd1 . 5 hr sa f t e r t r e a t me nt ,onl ydi s t i l l e dwa t e r5 ml / kgwa s o r a l l ya d mi ni s t e r e d ,i ns t e a do fGo ngj i nda ns us - pe ns i ons .Eac hdone pe z i lorGongj i nda nwa s

or a l l ya dmi ni s t e r e d,i navo l umeof5 m/ kg, di s s o l ve di ndi s t i l l e dwa t e r ,o nc eada yf o r7 da ys .

2 . 4 .Ch a n g e si nb o d ywe i g h t s

Cha nge so fbo d ywe i ghtwe r ed a i l yme a s u r e d f r o m 1d a yb e f o r ei n i t i a t i o no fc o -a d mi n i s t r a t i o n t ot hel a s t7 t hc o -a d mi ni s t r a t i o nda yus i nga n aut omat i ce l e c t r oni cbal anc e( Pr e c i s aI ns t - r ume nt ,Swi t z l a nd ) .Ati ni t i a t i o na ndl a s t7 t h a dmi ni s t r a t i o n,a l le xp e r i me nt a la ni ma l swe r e o ve r ni ghtf a s t e d( wa t e rwa sno t;a bo ut1 2 hr ) t or e duc et hedi f f e r enc e sf r om f e edi ng.I n addi t i on,bodywei ghtgai nsdur i ng co- a dmi ni s t r a t i onda ysa sbo dywe i ght sa tl a s t 7 t ht r e a t me ntda y-bo d ywe i ght sa tf i r s tt r e a - t me ntda y.

2 . 5 .Pl a s mac o l l e c t i o n s

Al lr a t swe r es l i ght l ya ne s t he s i aunde re t hyl

e t he r( Duks a nPur eChe mi c a l ,Se oul ,Kor e a)

a ndbl o o ds a mpl e s( 0 . 5ml )we r ec o l l e c t e di nt o

5 0 I U he p a r i ni z e dt ube svi at heo r bi t a lp l e xus a t3 0 mi nbe f o r et r e a t me nt( a sac o nt r o l ) ,3 0 mi n, 1 ,2 ,3 ,4 ,6 ,8a nd2 4 hr sa f t e re ndo ff i r s ta nd l a s t7 t hor ala dmi ni s t r a t i on.Bl o ods a mpl e s we r ei mme di a t e l yc e nt r i f uge df o r1 0mi na t 1 3 , 0 0 0r p m a nda bo ut0 . 3 mla l i quo t so fp l a s ma we r es t or edi na-70℃ de e pf r e e z e runt i l a na l ys i so fd o ne pe z i l .

2 . 6 .Sa mp l ep r e p a r a t i ona n d c a l i b r a t i o n s

Pr i ma r ys t o c ks o l ut i o n,1 . 0 mg/ mlo fd o ne - pe z i l i nac et oni t r i l e( Si gma,MO,USA)and i nt e r na ls t a nd a r dwo r ki ngs o l ut i o n,c a r ba ma - z e pi ne( Si gma ,MO,USA)5 0 0 ng/ mli nac e - t oni t r i l ewe r epr e par e d.Wor ki ng s t andar d s o l ut i o nswe r ep r e p a r e dbydi l ut i o nwi t ha c e - t o ni t r i l e .Al ls t a nd a r ds o l ut i o nswe r es t o r e da t -20℃ i n t hedar k whe n noti n us e ,and c al i br at e dt hes t andar ds a mpl e sas1 0 0 μ lof bl a nkp l a s ma ,wo r ki ngs t a nda r ds o l ut i o nsa nd i nt e r na ls t a nd a r dwo r ki ngs o l ut i o nwe r emi xe d wi t h1 0 0 μ lo fa c e t o ni t r i l e .Themi xt ur e swe r e mi xe dbyvor t e x-mi xi nga ndc e nt r i f uge dat 1 2 , 0 0 0 r pm f o r1 0 mi na t4 ℃.Thec l e a rs up e r - na t a nt swe r et r a ns f e r r e dt oi nj e c t i o nvi a l sa nd t hea l i quo twa si nj e c t e di nt ot heLC-MS/ MS s ys t e m.I na ddi t i o n,1 0 0 μ lo fs a mpl epl a s ma a ndi nt e r na ls t a nda r dwo r ki ngs o l ut i onwe r e mi xe dwi t h2 0 0 μ lo fa c e t o ni t r i l e .Themi xt ur e s we r emi xe dbyvo r t e x-mi xi nga ndc e nt r i f uge d a t1 2 , 0 0 0 r pm f o r1 0 mi na t4 ℃.Cl e a rs upe r - nat a nt s( 3 . 5 μ l )we r edi r e c t l y t r ans f e r r e dt o i nj e c t i onvi al sa ndt heal i quo twasi nj e c t e d i nt ot heLC-MS/ MSs ys t e m.

2 . 7 .L C- MS/ MSc o n d i t i o n s

Co nc e nt r a t i o nso fd o ne p e z i li nt her a tp l a s ma s a mp l e swe r ed e t e r mi ne dLC-MS/ MSme t ho d.

Chr o ma t o gr a p hi ca na l ys i swa sp e r f o r me dus i ng

a nAgi l e nt1 1 0 0Se r i e sHPLC( Agi l e ntTe c hno -

l o gi e s ,CA,USA)e q u i p p e dwi t ho n -l i n ed e ga s s e r ,

bi nar ypump,a ut os a mpl e ra ndc o l umnc om-

p a r t me n t .Se p a r a t i o no ft hea n a l yt ef r o m p o t e n-

t i al l yi nt e r f e r i ngmat e r i alwasac hi e ve dat

a mbi e ntt e mpe r a t ur eus i ngWa t e r sXt e r r aMS

C1 8 c o l umns( 2 . 1 ×5 0 mm,3 . 5 μ m)( Wa t e r sCo r p . ,

MA,USA)a tc o l umnove n3 0 ℃.Themobi l e

pha s eus e df o rt hec hr o ma t o gr a p hi cs e p a r a t i o n

wa sc o mpo s e do f2 % a c e t o ni t r i l e / 9 8 % di s t i l l e d

wa t e r( 0 . 1 % f o r mi ca c i d )t o9 8 % a c e t o n i t r i l e / 2 %

di s t i l l e dwat e r( 0 . 1 % f or mi cac i d) ,a ndwa s

de l i ve r e di s o c r a t i c a l l ya taf l o w r a t eo f0 . 3 5 ml /

mi n.Thec o l umne f f l ue ntwa smo ni t o r e dus i ng

a nAPI2 0 0 0t r i p l e -q ua d r up l ema s s -s p e c t o me t r i c

de t e c t o r( Ap pl i e dBi o s ys t e ms ,CA,USA) .The

i ns t r ume ntwa se qui pp e dwi t ha ne l e c t r o s p r a y

i nt e r f a c ei npo s i t i vei o nmo de ,a ndc o nt r o l l e d

byt heAna l ys tve r s i o n1 . 4 . 2s o f t wa r e( Ap pl i e d

Bi o s ys t e ms ,CA,USA) .Sa mpl e swe r ei nt r o -

d u c e dt ot h ei nt e r f a c et h r o ughaTu r b oI o nSp r a y

wi t ht het e mpe r a t ur es e ta t4 0 0 ° C.A hi gh

pos i t i vevol t a geof5 . 0kV wa sa ppl i e dt ot he

i o ns p r a y.Ni t r o ge nwa sus e da st hene bul i z e r

gas ,c ur t ai ngas ,andc ol l i s i ongaswi t ht he

s e t t i ngso f1 2 ,6 ,a nd8 ,r e s p e c t i ve l y.Themul -

t i p l er e a c t i o nmo n i t o r i n g( MRM)d e t e c t i o nme t h o d

wa se mpl oye df ort hede t e c t i o nofdo ne pe z i l

t het r a ns i t i o nsmo ni t o r e dwe r ec a r ba ma z e pi ne

( I S) :m/ z2 3 7 >1 9 4( Re t e nt i ont i me :2 . 4mi n) ,

done pe z i l :38 0>91( Re t e nt i ont i me :2. 3mi n) .

Ca l i br a t i o nc ur ve so fd o ne p e z i lwe r el i ne a ro ve r

Fi g1 .Ch e mi c a lSt r u c t u r eo fDo n e p e z i lUs e di nTh i sSt u d y

t her a nge ss t udi e dwi t hr

＞0 . 9 9 9 .Thel o we r l i mi tofqua nt i f i c a t i ono ft hedone pe z i li nt he r a tpl a s mawa s1 ng/ ml .

2 . 8 .Ph a r ma c o k i n e t i ca n a l y s i s

Thep l a s mac o nc e nt r a t i o nd a t awe r ea n a l yz e d us i nganonc o mpa r t me nt a lme t ho donc om- me r c i a lp h a r ma c o k i n e t i c sd a t aa na l yz e rp r o gr a ms ( PK s ol ut i ons2 . 0 ;Summi t ,CO,USA)

.The e l i mi na t i o nr a t ec o ns t a nt( K

)wa sc a l c ul a t e db y t hel o g-l i ne arr e gr e s s i o nofdone pe z i l c onc e n- t r a t i onda t adur i ngt hee l i mi na t i o npha s e , a nd t het e r mi na lha l f -l i f e( t

)wa sc a l c ul a t e dby 0 . 6 9 3 / K

.The pe a kc o nc e nt r a t i o n( Cma x)a nd t i met or e a c ht hepe a kc o nc e nt r a t i o n( Tma x) ofdone pe z i l i nt hepl a s mawe r eobt a i ne dby vi s u a l i n s p e c t i o no ft h ed a t ai nt h ec o n c e n t r a t i o n - t i me cur ve.Thear ea undert he pl asma c onc e nt r at i on-t i mec ur ve( AUC

)f r omt i me z e r ot ot het i meo ft hel a s tme a s ur e dc o nc e n- t r a t i o n( C

) wa sc a l c ul at e dus i ngt hel i ne a r

t r ape z oi dalr ul e

.TheAUCz e r ot oi nf i ni t y ( AUC

)wasobt ai ne dbyaddi ngAUC

a ndt hee xt r a po l a t e da r e awa sde t e r mi ne dby C

K

.Theme an r e s i de nc e t i mei nf i ni t y ( MRT

)wa sc a l c ul at e dbydi vi di ngt hef i r s t mome nto fAUC( AUMC

)byAUC

.

2 . 9 .St a t i s t i c a la n a l y s e s

Al lt heme a nsa r ep r e s e nt e dwi t ht he i rs t a n-

da r dde vi a t i o no ff i ver a t s( Me a n±SDo ff i ve

r a tpl as mac o nc e nt r a t i o nso fdo ne pe z i l ) .The

pha r mac oki ne t i cpa r ame t e r swe r ec ompar e d

us i ngano n-p a r a me t r i cc o mp a r i s o nt e s t ,Ma nn-

Whi t ne yU( MW)t e s t ,o nt heSPSSf o rWi n-

dows( Re l e as e14 . 0K,SPSS I nc . ,USA) .A

p-val ue<0. 05wasc onsi der e dst at i st i c al l y

s i gni f i c a nt .I na ddi t i on,t hepe r c e ntc ha nge s

be t we e nd o ne p e z i ls i ngl et r e a t e dr a t sa n dd o ne -

p e z i lwi t hGo ngj i nd a nc o -a d mi ni s t e r e dr a t swe r e

c a l c ul a t e dt ohe l pt heunde r s t a ndi ng oft he

e f f e c t so fc o -a dmi ni s t r a t i o n.

Fi g2 .Ex p e r i me n t a lDe s i g n sUs e di nTh i sSt u d y

Af t e r1 0 mg/ k go fd o ne p e z i lt r e a t me nt ,Go ngj i nd a n1 0 0 mg/ kgwa sa d mi ni s t e r e dwi t h1 . 5 -hr i nt e r va l s .I nd o ne p e z i ls i ngl et r e a t e dr a t s ,1 0 mg/ kg o fd o ne p e z i lwa so r a l l ya d mi ni s t e r e d a nd1 . 5 hr sa f t e rt r e a t me nt ,o nl y d i s t i l l e dwa t e r5 ml / kg wa so r a l l y a d mi ni s t e r e d,i ns t e a d o fGo ngj i nda ns us p e ns i o ns .Ea c hdo ne p e z i lo rGo ngj i nd a n wa so r a l l ya d mi ni s t e r e d,i na vo l umeo f5 m/ kg,di s s o l ve di ndi s t i l l e dwa t e r ,o nc eada y f o r7da ys ,a ndbl o o dswe r e s a mp l e da f t e rf i r s ta ndl a s t7 t hdo ne p e z i la dmi ni s t r a t i o n,r e s p e c t i ve l y.

3. Results

3 . 1 .Ch a n g e sont h ep l a s ma c o n c e n t r a t i o n so fd o n e p e z i l

Nome a ni ngf ulc ha nge so nt hebo d ywe i ght a ndga i nswe r ed e t e c t e di nGo ngj i nd a na ndd o n e - pe z i lc o -a dmi ni s t e r e dr a t sa sc o mpa r e dwi t h do ne p e z i ls i ngl et r e a t e dr a t st hr o ugho ute xp - e r i me nt a lpe r i o ds ,r e s p e c t i ve l y( Ta bl e2 ,Fi g3 ) .

3 . 2 .Ch a n g e sont h ep l a s ma c o n c e n t r a t i o n so fd o n e p e z i l Do ne p e z i lwa sd e t e c t e df r o m 3 0 mi nt o8 hr s

a f t e re ndo fa dmi ni s t r a t i o ni nt hebo t hd o ne - p e z i ls i n gl ea n dc o -a d mi ni s t e r e dr a t swi t hGo n- gj i n d a na f t e rf i r s ta n dl a s t7 t hc o -a d mi n i s t r a t i o n , r e s p e c t i ve l y.Go ngj i nd a ns i gni f i c a nt l y( p <0 . 0 1o r p<0 . 0 5 )i nhi bi t e dt hea bs o r p t i o no fdo ne p e z i l a t 2,4,6and8hr saf t e rf i r st1. 5hr -i nt e r val c o-a dmi ni s t r a t i ono fdone pe z i l 1 0 mg/ kgwi t h Go n gj i n d a n 1 0 0 mg/ k ga sc o mp a r e dwi t hd o n e p e z i l s i ngl et r e a t e dr a t s ,a ndt hea bs o r p t i o no fd o ne - pe z i lwe r ea l s ono n-s i gni f i c a ntbutma r ke dl y de c r e as e dat3 0 mi n,1a nd3hr sa f t e r1 . 5 hr - i nt e r va lc o-a dmi ni s t r a t i ona sc o mpa r e dwi t h do ne pe z i ls i ngl et r e at e dr at s ,i nt hepr e s e nt s t udy.Ho we ve r ,nome a ni ngf ulc ha nge so nt he pl a s mado ne p e z i lc o nc e nt r a t i o nswe r ede t e c t e d

Ta b l e2 .Bo d ywei g h tg a i n sd u r i n gAd mi n i s t r a t i o n( f r o m f i r s tt ol a s tt r ea t me n t )o fDo n e p e z i l wi t ha n dwi t h o u tGo n g j i n d a ni nMa l eRa t s

Gr o ups

Do ne pe z i l( 1 0 mg/ kg) Wi t ho utGo ngj i nd a nc o -a d mi ni s t r a t i o n

( Di s t i l lwa t e r )

Wi t hGo ngj i nd a nc o -a d mi ni s t r a t i o n ( 1 0 0 mg/ kg)

Bo dywe i ght s

Atf i r s tt r e a t me nt[ A] 2 2 3 . 8 0±4 . 8 2 2 2 2 . 8 0±6 . 0 6 Atl a s tt r e a t me nt[ B] 2 4 3 . 4 0±8 . 8 5 2 4 2 . 6 0±6 . 3 5 Bo dywe i ghtga i ns

[ B]– [ A] 1 9 . 6 0±6 . 3 9 1 9 . 8 0±3 . 1 9

Va l ue sa r ee xp r e s s e da sme a n±SD o ff i ver a t s

Fi g3 .Ch a n g e so nt h eBo d yWe i g h t sd u r i n g1 . 5 h r - i n t e r v a lCo - a d mi n i s t r a t i o no fDo n e p e z i lwi t h a n dwi t h o u tGo n g j i n d a ni nMa l eRa t s

Nome a ni ngf ulc ha nge so nt hebo d ywe i ghta ndga i nswe r ede t e c t e di nGo ngj i nda n a ndd o ne p e z i lc o -a d mi ni s t e r e dr a t sa sc o mp a r e dwi t hdo ne p e z i ls i ngl et r e a t e dr a t s t hr o u gho ute xp e r i me nt a lp e r i o d s ,i n t he p r e s e nts t ud y.Va l ue s a r e e xp r e s s e d a s me a n ± SD o ff i ver a t s .Al la ni ma l swe r eo ve r ni gh tf a s t e d b e f o r ef i r s ta ndl a s t t r e a t me nt .Be f o r e ,1d a ybe f o r ef i r s tt r e a t me ntD,d o ne p e z i lGJ D,Go ngj i nd a n.

i nGo n gj i nd a nc o -a d mi n i s t r a t e d r a t sa sc o mp a r e d wi t hdone pe z i ls i ngl et r e at e dr at saf t e rl as t 7 t h1 . 5 hr -i nt e r va lc o-admi ni s t r a t i on,e xc e pt f o rno n-s i gni f i c a nts l i ghti nc r e a s e so fpl a s ma do ne pe z i lc o nc e nt r a t i o nde t e c t e di nGo ngj i nd a n co-admi ni st r at ed r at sascompar ed wi t h do ne p e z i ls i ngl et r e a t e dr a t sa t1hra f t e rl a s t 7t h1. 5hr -i nt e r valco-admi ni st r at i on,i nt he p r e s e nts t udy( Fi g4a nd5 ) .

Thep l a s mad o ne p e z i lc o nc e n t r a t i o n sa t3 0 mi n, 1 ,2 ,3 ,4 ,6a nd8 hr sa f t e re ndo ff i r s t1 . 5 hr - i nt e r valc o -admi ni s t r at i o nwe r ec ha nge da s -2 6 . 8 9 ,-1 8 . 1 7 ,-2 9 . 6 9 ,-2 9 . 5 3 ,-2 7 . 8 8 ,-2 6 . 7 8a nd -2 5 . 7 1 % i nd o ne p e z i l+Go ngj i nd a nt r e a t e dr a t s a sc o mp a r e dwi t hd o ne p e z i ls i ngl et r e a t e dr a t s ,

r e s pe c t i ve l y.

Th ep l a s mad o n e p e z i lc o nc e nt r a t i o nsa t3 0 mi n, 1 ,2 ,3 ,4 ,6a n d8 hr sa f t e re ndo fl a s t7 t h1 . 5 hr - i n t e r va lc o -a d mi ni s t r a t i o nwe r ec h a nge da s9 . 9 7 , 1 6 . 4 5 ,-7 . 9 9 ,-7 . 3 9 ,-2 . 8 9 ,-1 4 . 6 9a nd-1 2 . 8 5 % i n d o ne p e z i l+Go ngj i n d a nt r e a t e dr a t sa sc o mp a r e d wi t hdo ne p e z i ls i ngl et r e a t e dr a t s ,r e s p e c t i ve l y.

3 . 3 .Ch a n g e so nt h eTma x o fd o n e p e z i l

TheTmaxofdone pe z i lwas s l i ght l yand

no n-s i gni f i c a nt l yde c r e a s e da s1 1 . 1 1 % i nc o -

a dmi ni s t r a t e dr a t swi t hdo ne p e z i l 1 0 mg/ kga nd

Go ngj i nd a n1 0 0 mg/ k g( 1 . 0 0 ±0 . 0 0 h r )a sc o mp a r e d

Fi g4 .Pl a s maCo n c e n t r a t i o n so fDo n e p e z i lwi t ha n dwi t h o u tGo n g j i n d a na f t e rFi r s tCo - a d mi n i s t r a t i o n wi t h1 . 5 h r - i n t e r v a l si nMa l eRa t s

Do ne p e z i lwa sd e t e c t e df r o m 3 0 mi nt o8 hr sa f t e re ndo fa d mi ni s t r a t i o ni nt hebo t h d o n e p e z i ls i n gl ea ndc o -a d mi n i s t e r e dr a t swi t hGo n gj i n d a na f t e rf i r s tc o -a d mi n i s t r a t i o n , r e s p e c t i ve l y.Go ngj i nda ns i gni f i c a nt l y( p<0 . 0 1o rp <0 . 0 5 )i nhi bi t e dt hea bs o r pt i o n o f d o ne p e z i la t2 ,4 ,6a nd8 hr sa f t e rf i r s t1 . 5 h r -i nt e r va lc o -a d mi ni s t r a t i o no fd o ne p e z i l 1 0 mg/ k gwi t hGo ngj i nd a n1 0 0 mg/ kga sc o mp a r e dwi t hd o ne p e z i ls i ngl et r e a t e dr a t s , a ndt hea bs o r p t i o no fd o ne p e z i lwe r ea l s ono n-s i gni f i c a ntb utma r k e d l yd e c r e a s e da t 3 0 mi n,1a nd3 hr sa f t e r1 . 5 hr -i nt e r va lc o -a d mi ni s t r a t i o na sc o mp a r e dwi t hd o ne p e z i l s i ngl et r e a t e dr a t s ,i nt h ep r e s e nts t ud y. Va l u e sa r ee xp r e s s e da sme a n±SD o ff i ve r a t s .D,d o ne p e z i lGJ D,Go n gj i nd a n .

p <0 . 0 1a nd

p <0 . 0 5a sc o mp a r e dwi t hd o n e p e z i l s i ngl et r e a t e dr a t sbyMW t e s t

wi t hd o ne p e z i ls i ngl et r e a t e dr a t s( 0 0 . 9 0 ±0 . 6 5 hr ) a f t e re n do ff i r s t1 . 5 h r - i n t e r va lc o -a d mi n i s t r a t i o n o fd o ne pe z i l1 0 mg/ kgwi t hGo ngj i nda n1 0 0 mg/

kg.Howeve r ,t heTmaxofdone pe z i lwas s l i ght l yandnon-s i gni f i c ant l yi nc r e as e das 1 6 . 6 7 % i n1 . 5 hr -i nt e r va l sc o -a d mi ni s t r a t e dr a t s wi t hdo ne pe z i la ndGongj i nda n( 0 . 7 0 ±0 . 2 7 hr ) a sc o mp a r e dwi t hdo ne p e z i ls i ngl et r e a t e dr a t s ( 0 . 6 0 ±0 . 2 2 hr )a f t e re ndo fl a s t7 t h1 . 5 hr -i nt e r va l

c o -a dmi ni s t r a t i onofdo ne pe z i l1 0 mg/ kgwi t h Gongj i nda n1 0 0 mg/ kg,i nt hepr e s e nts t udy ( Ta bl e3a nd5 ) .

3 . 4 .Ch a n g e so nt h eCma x o fd o n e p e z i l

TheCma xo fd o ne p e z i lwa sno n -s i gn i f i c a nt l y

butmar ke dl yde c r e as e das-2 6. 23 % i nc o-

Fi g5 .Pl a s maCo n c e n t r a t i o n so fDo n e p e z i lwi t ha n dwi t h o u tGo n g j i n d a na f t e rL a s t7 t hCo - a d mi n i s t r a t i o n wi t h1 . 5 h r - i n t e r v a l si nMa l eRa t s

Do n e p e z i lwa sd e t e c t e df r o m 3 0 mi nt o8 h r sa f t e re n d o fa d mi n i s t r a t i oni nt h eb o t hdo n e p e z i ls i n g l e a n dc o - a d mi n i s t e r e dr a t swi t hGo n g j i n d a na f t e rl a s t7 t hc o - a d mi n i s t r a t i o n ,r e s p e c t i v e l y .Nome a n i n g f u l c h a n g e so nt h ep l a s mad o n e p e z i lc o n c e n t r at i o n swe r ed e t e c t e di nGo n g j i n d a nc o - a d mi n i s t r a t e dr a t s a sc o mp a r e dwi t hd o n e p e z i ls i n g l et r e a t e dr a t sa f t e rl a s t7 t h1 . 5 h r - i n t e r v a lc o - a d mi n i s t r a t i o n ,e x c e p t f ornon-s i gni f i c ants l i ghti nc r eas esofpl as madonepez i lc onc ent r at i ondet ec t edi nGongj i ndan c o- ad mi ni s t r at e dr at sasc ompar edwi t hdo ne pe z i ls i ng l et r e at edr a t sat1h raf t erl as t7 t h1 . 5 h r - i n t e r v a lc o - a d mi n i s t r a t i o n ,i nt h ep r e s e n ts t u d y . Va l u e sa r ee x p r e s s e da sme a n± SD o ff i v er a t s .D, d o n e p e z i lGJ D,Go n g j i n d a n .

a d mi ni s t r a t e dr a t swi t hd o ne p e z i l1 0 mg/ kga nd Go ngj i nd a n1 0 0 mg/ k g( 1 5 5 . 8 0 ±1 8 . 7 4 n g)a sc o m- p a r e dwi t hd o n e p e z i ls i n gl et r e a t e dr a t s( 2 1 1 . 2 0 ± 5 4 . 7 9 ng)af t e re ndoff i r s t1 . 5 hr -i nt e r va lc o- a d mi ni s t r a t i o n.Ho we ve r ,t heCma xo fd o n e p e z i l wa ss l i ght l ya ndno n-s i gni f i c a nt l yi nc r e a s e da s 1 0 . 9 4 % i nGongj i nda nc o-a dmi ni s t r a t e dr a t s ( 2 4 1 . 4 0 ±2 3 . 3 1 ng)a sc ompar e dwi t hdone pe z i l s i ngl et r e a t e dr a t s( 2 1 7 . 6 0 ±3 5 . 3 2 ng)a f t e re nd o fl a s t7 t h1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n,i n t hep r e s e nts t udy( Ta bl e3a nd5 ) .

3 . 5 .Ch a n g e so nt h eAUC o fd o n e p e z i l

TheAUC

a ndAUC

o fdo ne p e z i lwe r e

s i gni f i c a nt l y( p <0 . 0 5 )de c r e a s e da s-2 6 . 0 2a nd

-2 5 . 9 0 % i nc o -a d mi ni s t r a t e dr a t swi t hd o ne p e z i l

1 0 mg/ kga ndGo ngj i nda n1 0 0 mg/ kg( 4 5 3 . 9 0 ±

4 7 . 4 0a nd4 7 6 . 3 3 ±5 0 . 8 2hr ․ng/ ml )a sc o mp a r e d

wi t hd o ne p e z i ls i ngl et r e a t e dr a t s( 6 1 3 . 5 4 ±8 7 . 8 5

a nd6 4 2 . 7 8 ±9 5 . 3 3 hr ․ng/ ml )a f t e re ndo ff i r s t

1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n.Ho we ve r ,t he

Ta b l e3 .Ph a r ma c o k i n e t i cPa r a me t e r so fDo n e p e z i lwi t ha n dwi t h o u tGo n g j i n d a na f t e r Fi r s tCo - a d mi n i s t r a t i o nwi t h1 . 5 h r - i n t e r v a l si nMa l eRa t s

Pa r a me t e r s

Do ne p e z i l( 1 0 mg/ kg) Wi t ho utGo ngj i nda nc o -a dmi ni s t r a t i o n

( Di s t i l lwa t e r )

Wi t hGo ngj i nda n c o -a d mi ni s t r a t i o n( 1 0 0 mg/ kg) Tma x( hr s ) 0 . 9 0±0 . 6 5 1 . 0 0±0 . 0 0

Cma x( ng/ ml ) 2 1 1 . 2 0±5 4 . 7 9 1 5 5 . 8 0±1 8 . 7 4 AUC

( hr ․ng/ ml ) 6 1 3 . 5 4±8 7 . 8 5 4 5 3 . 9 0±4 7 . 4 0

AUC

( hr ․ng/ ml ) 6 2 4 . 7 8±9 5 . 3 3 4 7 6 . 3 3±5 0 . 8 2

t

( hr ) 1 . 7 5±0 . 2 1 1 . 8 0±0 . 1 0 MRT

( hr ) 2 . 7 3±0 . 2 5 2 . 7 1±0 . 0 7

Va l ue sa r ee xp r e s s e da sme a n±SD o ff i ver a t s .Cma x:Thep e a kp l a s mac o nc e nt r a t i o n,Tma x:Ti met o r e a c hCma x,AUC0 -t :Thet o t a la r e aund e rt hep l a s mac o nc e nt r a t i o n-t i mec ur vef r o m t i mez e r ot ot i me me a s ur e d,AUC0 -i nf :Thet o t a la r e aunde rt hep l a s mac o nc e nt r a t i o n-t i mec ur vef r o m t i mez e r ot ot i me i nf i ni t y,t 1 / 2 :ha l fl i f e ,MRTi nf :me a nr e s i de nc et ot i mei nf i ni t y.

p<0 . 0 5a sc o mpa r e dwi t hdo ne p e z i l s i ngl et r e a t e dr a t sbyMW t e s t

Ta b l e4 .Ph a r ma c o k i n e t i cPa r a me t e r so fDo n e p e z i lwi t ha n dwi t h o u tGo n g j i n d a n a f t e rL a s t7 t hCo - a d mi n i s t r a t i o nwi t h1 . 5 h r - i n t e r v a l si nMa l eRa t s Pa r a me t e r s

Done pe z i l( 1 0 mg/ kg) Wi t ho utGo ngj i nd a nc o -a d mi ni s t r a t i o n

( Di s t i l lwa t e r )

Wi t hGo ngj i nda nc o -a dmi ni s t r a t i o n ( 1 0 0 mg/ kg)

Tma x( hr s ) 0 . 6 0±0 . 2 2 0 . 7 0±0 . 2 7 Cma x( ng/ ml ) 2 1 7 . 6 0±3 5 . 3 2 2 4 1 . 4 0±2 3 . 3 1 AUC

( hr ․ng/ ml ) 6 3 2 . 2 1±4 5 . 7 4 6 5 6 . 7 9±1 1 . 7 2 AUC

( hr ․ng/ ml ) 6 7 2 . 3 5±5 8 . 5 6 7 1 0 . 8 4±4 9 . 1 1 t

( hr ) 1 . 9 0±0 . 2 5 2 . 1 5±0 . 5 3 MRT

( hr ) 2 . 9 4±0 . 2 7 3 . 0 8±0 . 6 8

Va l ue sa r ee xp r e s s e da sme a n±SD o ff i ver a t s .Cma x:Thep e a kp l a s mac o nc e nt r a t i o n,Tma x:Ti me t or e a c hCma x,AUC

:Th et o t a la r e aun d e rt h ep l a s mac o nc e n t r a t i o n-t i mec u r vef r o m t i mez e r ot ot i me me a s ur e d ,AUC

:Thet o t a la r e aunde rt hep l a s mac o nc e nt r a t i o n-t i mec ur vef r o m t i mez e r ot ot i me i nf i ni t y,t

:ha l fl i f e ,MRTi nf :me a nr e s i de nc et ot i mei nf i ni t y

AUC

andAUC

ofdone pe z i lwe r eno me a ni ngf ul l yc ha nge da s3 . 8 9a nd5 . 7 2 % i n co-admi ni st r at edr at swi t hdonepez i land Go ngj i nda n( 6 5 6 . 7 9 ±1 1 . 7 2a nd7 1 0 . 8 4 ±4 9 . 1 1 hr ․ ng/ ml )ascompar e dwi t hdonepez i lsi ngl e t r e a t e dr a t s( 6 3 2 . 2 1 ±4 5 . 7 4a nd6 7 2 . 3 5 ±5 8 . 5 6 hr ․ ng/ ml )a f t e re ndo fl a s t7 t h1 . 5 hr -i nt e r va lc o - a dmi ni s t r a t i o n,i nt hep r e s e nts t udy( Ta bl e3

a nd5 ) .

3 . 6 .Ch a n g e so nt h et

ofd o n e p e z i l

Thet

ofdonepezi lwassl i ght l y and

no n-s i gni f i c a nt l yi nc r e a s e da s3 . 4 0 % i nc o-

a dmi ni s t r a t e dr a t swi t hdo ne p e z i l1 0 mg/ kga nd

Go ngj i nda n1 0 0 mg/ kg( 1 . 8 0 ±0 . 1 hr )a sc o mp a r e d

wi t hdo ne p e z i ls i ngl et r e a t e dr a t s( 1 . 7 5 ±0 . 2 1 hr ) a f t e re n do ff i r s t1 . 5 hr -i n t e r va lc o -a d mi ni s t r a t i o n.

I na d d i t i o n ,t het

o fd o ne p e z i lwa sa l s os l i gh t l y a ndno n-s i gni f i c a nt l yi nc r e a s e da s1 3 . 1 6 % i n c o -a dmi ni s t r a t e dr a t swi t hd o ne p e z i la ndGo n- gj i n d a n( 2 . 1 5 ±0 . 5 3 h r )a sc o mp a r e dwi t hd o n e p e z i l s i ngl et r e a t e dr a t s( 1 . 9 0 ±0 . 2 5 hr )a f t e re n do fl a s t 7 t h1 . 5hr -i nt e r valc o-admi ni s t r at i on,i nt he p r e s e nts t udy( Ta bl e3a nd5 ) .

3 . 7 .Ch a n g e sont h eMRT

o fd o n e p e z i l

TheMRT

o fd o ne p e z i lwa sno n-s i gni f i c a nt l y c h a n ge da s-0 . 7 7 % i nc o -a d mi ni s t r a t e dr a t swi t h do ne pe z i l1 0 mg/ kga ndGo ngj i nda n1 0 0 mg/ kg ( 2 . 7 1 ±0 . 0 7 hr )a sc o mp a r e dwi t hdo ne p e z i ls i ngl e t r e a t e dr a t s( 2 . 7 3 ±0 . 2 5 hr )a f t e re ndo ff i r s t 1 . 5 hr -i nt e r va lc o -a d mi ni s t r a t i o n .I na d d i t i o n ,t h e MRT

o fdo ne p e z i lwa sa l s ono n-s i gni f i c a nt l y c ha nge da s4 . 6 9 % i nc o -a d mi ni s t r a t e dr a t swi t h donepe z i landGongj i ndan( 3. 08±0. 68hr )as c o mpa r e dwi t hdo ne pe z i ls i ngl et r e a t e dr a t s ( 2 . 9 4 ±0 . 2 7 hr )a f t e re ndo fl a s t7 t h1 . 5 hr -i nt e r va l c o -a dmi ni s t r a t i o n,i nt hep r e s e nts t udy( Ta bl e 3a nd5 ) .

4. Discussion

Al t houghdone pe z i li sac e nt r al l yac t i ng r e ve r s i bl ea c e t yl c ho l i ne s t e r a s ei nhi bi t o r ,f r e - que nt l yus e df orpa l l i a t i vet r e a t me ntofmi l d t omo d e r a t eAl z he i me r ’ sd i s e a s e

a ndf o rs ym- p t o ma t i ct r e a t me nto fpa t i e nt swi t hmi l d ,mo - de r a t ea nds e ve r ede me nt i ao ft heAl z he i me r ’ s t ype

,i tal s os howe ds e ver et oxi c i t y i n p r e c l i ni c a ls t ud i e s

a ndund e s i r a bl es i d ee f f e c t s

i nc l i ni c a lus e

.I na dd i t i o n,do ne p e z i lha s b e e ns h o we dva r i o u sd r ug-d r u gi n t e r a c t i o ns

, b utt hei nt e r a c t i o nswi t hhe r b a ln a t ur a lp r o d uc t s ha veno tb e e ne s t a bl i s he de xc e p tf o rs o mer e s - t r i c t e ds i ngl ehe r be xt r ac t sorna t ur alc o m- pounds

.Gongj i nda n,at r a di t i ona lKo r e a n po l yhe r ba lf o r mul ai so neo ft hemo s tf a mo us t o ni ca ge nt sa ndt hehyp o l i p i d e mi ca ndi mmune s t i mul a t o r y

,a nt i -o xi da t i ve

,a nt i -gl i o s i s e f f e c t s

and ant i -de me nt i ae f f e c t s

of Go ngj i nd a na r er e l a t i ve l ywe l ldo c ume nt e d.

I n t hep r e vi o uss t ud y

,c o -a dmi ni s t r a t i o n ofGongj i nda n wi t h do ne pe z i lwi t hi n 5 mi n s h o we dma r ke dd e c r e a s e so fd o n e p e z i la bs o r p t i o n a nd c o ns e que nt l y,r e d uc e dt heo r a lbi o a va i l - a bi l i t y o fdo ne p e z i l ,t he r e f o r e ,t hee f f e c t so f Go n gj i n d a nc o -a dmi ni s t r a t i o no nt hepha r ma -

c o ki ne t i c so fdo ne pe z i lwe r eo bs e r ve da f t e r s i ngl ea nd7 - d a yr e p e a t e do r a lc o -a d mi ni - s t r a t i o nwi t h1 . 5 hr -i nt e r va l sa sapr o c e s so f t hec o mpr e he ns i vea ndi nt e gr a t i veme di c i ne , c o mb i n a t i o nt h e r a p yo fd o n e p e z i lwi t hGo n g j i n d a n t o a c h i e ves y n e r gi cp ha r ma c o d yna mi c sa ndr e d uc e t o xi c i t yi nt hep r e s e nts t ud y.Af t e r1 0 mg/ kgo f d o n e p e z i lt r e a t me nt ,Go ngj i nda n1 0 0 mg/ kgwa s a dmi ni s t e r e dwi t h1 . 5 h r -i nt e r va l s .Thep l a s ma we r ec o l l e c t e da t3 0 mi nbe f o r ea dmi ni s t r a t i o n, 3 0 mi n,1 ,2 ,3 ,4 ,6 ,8a nd2 4 hr sa f t e re ndo f f i r s ta nd l a s t7 t h do ne p e z i lt r e a t me nt ,a nd pl as ma c onc e nt r at i ons ofdone pe z i lwe r e anal yz e dusi ngLC-MS/ MS met hods.PK pa r ame t e r s o fdone pe z i lwe r e a na l ys i s a s c ompar e d wi t h done pe z i ls i ngl eadmi ni - s t e r e dr a t sus i ngno nc o mpa r t me nt a lp ha r ma - c o ki ne t i c sda t aa na l yz e rp r o gr a ms .

Go ngj i nda nma r ke dl yi nhi bi t e dt hea bs o r p-

t i ono fdone pe z i lr e ga r dl e s sofs a mpl et i me ,

f r o m 3 0 mi nt o8 hr sa f t e re ndo ff i r s t1 . 5 hr -

i nt e r va lc o-a dmi ni s t r a t i ona sc ompar e dwi t h done pe z i ls i ngl et r e a t e dr a t s .Es pe c i a l l yt he a bs o r pt i o no fdo ne p e z i lwe r es i gni f i c a nt l y( p<

0 . 0 5 )de c r e a s e da t2 ,4 ,6a nd8 hr sa f t e rc o- admi ni s t r a t i on a sc ompa r e dwi t hdone pe z i l s i ngl et r e at e dr at s .Ac c or di ngl y,t heCmax ( -26 . 2 36 %) ,AUC

( -26 . 02%)andAUC

( -2 5 . 9 0 %)ofdone pe z i li n1 . 5 hr -i nt e r va lc o- a dmi ni s t e r e dr a t swe r ed r a ma t i c a l l yde c r e a s e d asc ompar e dwi t hdone pe z i ls i ngl et r e at e d r at s ,r e s pe c t i ve l y.Howe ve r ,nome ani ngf ul c hange sont hepl as madone pe z i lc onc e nt - r a t i o nsa ndp ha r ma c o ki ne t i cpa r a me t e r swe r e d e t e c t e da f t e re ndo fl a s t7 t h1 . 5 hr -i nt e r va lc o - a d mi n i s t r a t i o na sc o mp a r e dwi t hd o n e p e z i ls i n gl e t r e a t e dr a t s ,e xc e p tf o rno n-s i gni f i c a nts l i ght i nc r e a s e sofTmax( 1 6 . 6 7 %)de t e c t e di nc o - a dmi ni s t e r e dr a t sa sc o mp a r e dwi t hd o ne pe z i l s i ngl et r e a t e dr a t s .The s ef i ndi ngsa r ec on- s i de r e da sdi r e c te vi de nc e st hatGongj i nda n a l s ode c r e a s e do r a lbi o a va i l a bi l i t yo fdo ne p e z i l a si nhi bi t e dt hea bs o r pt i o ns ,whe nt he ywe r e co-admi ni st er edwi t h1. 5hr -i nt er val sas p r e vi o us5 mi nc o -a d mi ni s t r a t i o ns t ud y

,but t he yma ybea da pt e da f t e r7da ysc o nt i nuo us r e pe a t e d1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n.

Al lr a t sus e di nt hi ss t udy,s ho we dno r ma l bo dywe i ghti nc r e a s e sr a nge di nno r ma la ge - ma t c he dr a t sr e ga r dl e s so ft r e a t me nti nt he p r e s e nts t ud y

.I na dd i t i o n,nome a ni ngf ul c ha nge so nt hebo dywe i ghta ndga i nswe r e det ect edi nGongj i ndananddonepez i lco- a dmi ni s t e r e dr a t sa sc o mp a r e dwi t hd o ne pe z i l s i ngl et r e at e dr a t st hr oughoute xpe r i me nt al p e r i o ds ,i nt hep r e s e nts t udy.

Do ne p e z i lwa swe l la bs o r be d,wi t har e l a t i ve or a lbi oa va i l abi l i t yo f1 0 0 %

.Ther a t ea nd e xt e ntofa bs or pt i ona r enoti nf l ue nc e dby

f oodi nt a keort het i meofa dmi ni s t r at i on

. Do ne pe z i ls ho we dve r yhi ghpr o t e i nbi ndi ngs , i ts h o we da p p r o xi ma t e l y9 6 % p r o t e i nb i n d i ngs

, ma i nl yt oa l bumi ns( a bo ut7 5 %)a nd α 1 -a c i d gl yc o p r o t e i n( a bo ut2 1 %) .Tma xo fdo ne p e z i l i nhuma ns ubj e c ta f t e ro r a la dmi ni s t r a t i o ni s3 t o4ho ur sa nds l o wl ye l i mi na t e dt hr o ughr e na l a n db i l i a r ys ys t e m

,t 1 / 2o fd o n e p e z i li nh e a l t h y huma n vo l unt e e r si sa bo ut7 0ho ur s

.I n r at s,Tmaxofdone pe z i li s0 . 5～1hraf t e r s i ngl eor a la dmi ni s t r a t i ona ndt 1 / 2i sa bout 2 ～3hr s

.

I nt hep r e s e nts t udy,Tma xo fdo ne p e z i li n do ne p e z i ls i ngl eo r a lt r e a t e dr a t swa sde t e c t e d as0. 90 ±0. 6 5hraf t e rf i r s t1 . 5 hr -i nt e r valc o- admi ni s t r a t i on,a ndCma x,AUC

,AUC

, t

and MRT

we r e de t e c t e d as 2 11. 2 0±

5 4 . 7 9 n g,6 1 3 . 5 4 ±8 7 . 8 5 h r ․n g/ ml ,6 4 2 . 7 8 ±9 5 . 3 3 h r ․ ng/ ml ,1 . 7 5 ±0 . 2 1 hra nd2 . 7 3 ±0 . 2 5 hra f t e rf i r s t 1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n,r e s pe c t i ve l y.

I nd o ne pe z i lwi t hGo ngj i nda nc o -a d mi ni s t e r e d r a t s ,Tma x,Cma x,AUC

,AUC

,t

and MRT

ofdone pe z i lwe r ede t e c t e das1 . 0 0 ± 0 . 0 0 hr ,1 5 5 . 8 0 ±1 8 . 7 4 ng,4 5 3 . 9 0 ±4 7 . 4 0 hr ․ng/ ml , 4 7 6 . 3 3 ±5 0 . 8 2hr ․ng/ ml ,1 . 8 0 ±0 . 1 0 hra nd2 . 7 1 ± 0 . 0 7 hrc ha nge da s1 1 . 1 1 ,-2 6 . 2 3 ,-2 6 . 0 2 ,-2 5 . 9 0 , 3 . 4 0a nd-0 . 7 7 % a sc o mpa r e dwi t hdone pe z i l 10 mg/ kgs i ngl eor alt r e at e dr at saf t e rf i r s t 1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n,r e s pe c t i ve l y.

Especi al l y,t he AUC

and AUC

of

done pe z i li ndone pe z i lwi t hGongj i ndanc o-

a dmi ni s t e r e dr a t swe r es i gni f i c a nt l y( p<0 . 0 5 )

de c r e a s e da sc o mp a r e dwi t hdo ne p e z i ls i ngl e

t r e at ed r at saf t erf i r s t1. 5hr -i nt er valc o-

a dmi ni s t r a t i o n,r e s p e c t i ve l y.I na d di t i o n,Tma x

o fdo ne p e z i li n do ne p e z i ls i ngl eo r a lt r e a t e d

r a t swa sd e t e c t e da s0 . 6 0 ±0 . 2 2 hra f t e rl a s t7 t h

1 . 5 hr -i nt e r valc o-a dmi ni s t r at i on,a ndCma x,

AUC

,AUC

,t

a ndMRT

we r ed e t e c t e d as217. 60±35. 32ng,632. 21±45. 74hr ․ng/ ml , 6 7 2 . 3 5 ±5 8 . 5 6 hr ․ng/ ml ,1 . 9 0 ±0 . 2 5 hra nd2 . 9 4 ± 0. 27hraf t erl ast7t h 1. 5hr -i nt er valco- a dmi ni s t r a t i o n,r e s pe c t i ve l y.I ndo ne p e z i lwi t h Go ngj i nd a nc o -a d mi ni s t e r e dr a t s ,Tma x,Cma x, AUC

,AUC

,t

a ndMRTi nfo fdo ne p e z i l we r ede t e c t e da s0 . 7 0 ±0 . 2 7 hr ,2 4 1 . 4 0 ±2 3 . 3 1 ng, 6 5 6 . 7 9 ±1 1 . 7 2hr ․ng/ ml ,7 1 0 . 8 4 ±4 9 . 1 1 hr ․ng/ ml , 2 . 1 5 ±0 . 5 3 hra nd3 . 0 8 ±0 . 6 8 hrc ha nge da s1 6 . 6 7 , 1 0 . 9 4 ,3 . 8 9 ,5 . 7 2 ,1 3 . 1 6a nd4 . 6 9 % a sc o mpa r e d wi t hd o ne p e z i l1 0 mg/ kgs i ngl eo r a lt r e a t e dr a t s a f t e rl a s t7 t h1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n a ss i mi l a rt ot ho s eo fdo ne p e z i ls i ngl et r e a t e d r a t s ,r e s pe c t i ve l y.

Do ne p e z i lunde r go e sf i r s tp a s sme t a bo l i s m t of o urma j o rme t a bo l i t e s ,t woo fwhi c ha r e kno wnt obea c t i ve ,a ndanumbe ro fmi no r me t abol i t e s

.Done pe z i li sme t abol i z e dby c yt oc hr omeP45 0i s oe nz yme sCYP2 D6a nd CYP3 A4

a nd,t he r e f or e ,do ne pe z i lc a nbe i nt e r a c t e d wi t h o t he r dr ugs a c t o n t he s e i s o e nz yme s

.Af t e rf i r s tc o -a d mi ni s t r a t i o no f Go ngj i nda nwi t h1 . 5 hr -i nt e r va l s , t hea bs o r pt i o n o fdo ne pe z i lwa sa l s odr a ma t i c a l l yde c r e a s e d, qui t es i mi l art ot hos eofc o-admi ni s t r at i on wi t hi n5 mi n

i nt hep r e s e nts t ud y.I t ,t he r e f o r e , c o n s i d e r e dt ha t1 . 5 hr -i nt e r va lc o -a d mi n i s t r a t i o n wi t hGo n gj i nd a na l s oc a nb er e d uc e dt het o xi c i t y o rs i d ee f f e c t so fd o ne p e z i l

be c a us et o xi c i t y o rs i dee f f e c t so fd o ne p e z i lwe r e di r e c t l yr e l a t e d t ot hepl a s mac o nc e nt r a t i o ns .Ho we ve r ,i ta l s o o bvi o use vi de nc e st ha tt her e duc t i o no fdo ne - pe z i labs or pt i onsi nduc e dt hede c r e as e sof p ha r ma c o dyna mi c s .Al t ho ugha da p t i o nt r e nds wer edet ect ed af t er7-day r epeat ed co- a d mi ni s t r a t i o nwi t h1 . 5 hr -i nt e r va l s-nome a n- i ngf ulc ha nge so nt hepl a s mado ne pe z i lc o n-

c e nt r a t i onsa ndpha r ma c oki ne t i cpa r a me t e r s we r ede t e c t e d a f t e re ndofl as t7 t h 1 . 5 hr - i nt e r va lc o -a d mi ni s t r a t i o nwi t hGo ngj i nd a na s c o mpa r e dwi t hdo ne p e z i ls i ngl et r e a t e dr a t si n t hepr e s e nts t udy,i ta l s oo bs e r ve dt ha tGo ng- j i nda na l s ode c r e a s e st heor a lbi o a va i l a bi l i t y o fdo ne p e z i la si nhi bi t e dt hea bs o r pt i o na f t e r e ndo ff i r s t1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o n, qui t es i mi l a ra sr e s ul t so ft hep r e vi o us5 mi n c o -a d mi ni s t r a t i o ns t ud y

.The r e f o r e ,i ts e e ms t one e dc o-admi ni s t r at i onphar mac oki ne t i c s t udi e swi t h mor epr ol ong i nt e r val st han 1 . 5 hr s ,pr i ort ot hepha r mac odyna mi c sasa pr oc es sofcompr e hens i veandi nt e gr at i ve me di c i ne ,c ombi nat i ont he r apyofdone pe z i l wi t hGo ngj i nd a n.Mo r ede t a i lp ha r ma c o ki ne t i c s t udi e ss houl dbet e s t e dast hee f f e c t sof Go ngj i nd a no nt hepha r ma c o ki ne t i c so fdo ne - pe z i l ,whe nt he ywe r ec o -a dmi ni s t e r e dwi t h mo r ep r o l o ngi nt e r va l st ha nMRT

o fd o ne - pe z i ls i ngl eor aladmi ni s t r a t i on( about3 hr - i nt e r va l s )a nda f t e rr e p e a t e dc o -a d mi ni s t r a t i o ns .

5. Conclusion

Al t houghnomeani ngf ulchange sont he

p l a s mad o n e p e z i lc o nc e nt r a t i o nsa n dp h a r ma c o -

ki ne t i cp a r a me t e r swe r ede t e c t e da f t e re ndo f

l a s t7 t h1 . 5 hr -i nt e r va lc o -a dmi ni s t r a t i o nwi t h

Go ngj i nd a na sc o mp a r e dwi t hdo ne p e z i ls i ngl e

t r e a t e dr a t s ,i ta l s oo bs e r ve dt ha tGo ngj i nda n

a l s ode c r e a s e st he o r a lbi o a va i l a bi l i t yo fdo ne -

pe z i la si nhi bi t e dt hea bs o r p t i o na f t e re ndo f

f i r s t1 . 5 hr -i nt e r valc o-admi ni s t r at i on,qui t e

s i mi l a rasr e s ul t so ft hepr e vi ous5 mi nc o-

a dmi ni s t r a t i o ns t udy

,ba s e do nt her e s ul t so f

t hepr e s e nts t udy.He nc e ,i ts e e mst one e d

c o -a d mi ni s t r a t i o np ha r ma c o ki ne t i cs t ud i e swi t h mo r epr o l ongi nt e r va l st han1 . 5 hr s ,pr i o rt o t hepha r ma c o dyna mi c sa sap r o c e s so fc o mp- r e he ns i vea n di nt e gr a t i veme d i c i ne ,c o mbi n a t i o n t he r a pyo fdone pe z i lwi t hGongj i nda n.Iand myc o l l e a gue ss t r ongl ys ugge s t e dt ha tpha r - ma c o ki ne t i cs t ud i e ss ho ul dbet e s t e dl i ket he e f f e c t so fGo ngj i nd a no nt hep ha r ma c o ki ne t i c s o fdo ne p e z i l ,whe nt he ywe r ec o -a d mi ni s t e r e d wi t hmor epr ol ongi nt e r va l st hanMRT

of d o ne p e z i ls i ngl eo r a la d mi ni s t r a t i o n( a b o ut3 hr - i n t e r va l s )a nda f t e rr e p e a t e dc o -a d mi ni s t r a t i o ns

Acknowledgments

Thi ss t udy wassuppor t e d by gr antof Ko r e ao fHe a l t h& We l f a r e ,Re p ubl i co fKo r e a ( Pr o j e c tNo:2 0 -1 1 -0 -0 9 0 -0 9 1 -3 0 0 0 -3 0 3 3 -3 2 0 ) .

참고문헌

1 .Bi r k sJ ,Ha r ve yRJ .Do ne p e z i lf o rd e me n t i a d u et oAl z h e i me r ’ sd i s e a s e .Co c h r a n ed a t a - ba s eo fs ys t e ma t i cr e vi e ws( Onl i ne ) .2 0 0 6 ( 1 ) : CD0 0 1 1 9 0

2 .Ro ge r sSL.Pe r s p e c t i ve si nt h ema n a ge me nt o fAl z he i me r ’ sdi s e a s e :c l i ni c a lpr o f i l eof d o ne p e z i l .De me n t i aa ndge r i a t r i cc o gni t i ve d i s o r d e r s .1 9 9 8 ; 9Sup p l3 : 2 9 -4 2

3 .Ro ma nGC,Ro ge r sSJ .Do ne p e z i l :ac l i ni c a l r e vi e w o fc u r r e nta nde me r gi ngi nd i c a t i o ns . Exp e r to p i n i o no np h a r ma c o t he r a p y.2 0 0 4 ; 5 ( 1 ) : 1 6 1 -1 8 0

4 .Roj as -Fe r nande zCH.Suc c e s s f ulus eof d o n e p e z i lf o rt h et r e a t me n to fd e me n t i awi t h Le wybo di e s .TheAnna l sofpha r ma c o - t he r a p y.2 0 0 1 ; 3 5 ( 2 ) : 2 0 2 -2 0 5

5 .Ma l o ufR,Bi r ksJ .Do ne p e z i lf o rva s c u l a r c o gni t i vei mpa i r me nt .Co c hr a neda t a ba s e o fs ys t e ma t i cr e vi e ws( Onl i ne ) .2 0 0 4 ( 1 ) : CD 0 0 4 3 9 5

6 .Mo r a e sW,Po ya r e sD,Sukys -Cl a udi noL, Gui l l e mi na ul tC,Tuf i kS.Do ne pe z i li mp- r o ve so b s t r uc t i ves l e e pa p ne ai nAl z he i me r d i s e a s e :ad o ubl e -bl i nd ,p l a c e b o -c o nt r o l l e d s t u d y.Ch e s t .2 0 0 8 ; 1 3 3 ( 3 ) : 6 7 7 -6 8 3

7 .Ri e de lG,Ka ng SH,Cho iDY,Pl a t tB.

Sc opol ami ne -i nduc edde f i c i t si nsoci al me mor yi nmi c e :r e ve r s a lbydone pe z i l . Be havi our albr a i nr e s e a r c h.2 0 09 ; 2 0 4 ( 1 ) : 2 1 7 -2 2 5

8 .Ha n d e nBL,J o hns o nCR,Mc Aul i f f e -Be l l i n S,Mur r ayPJ ,Har danAY.Saf e t yand e f f i c a c yo fd o ne p e z i li nc hi l d r e na nda d o - l e s c e nt swi t ha ut i s m:ne ur o ps yc ho l o gi c a l me a s ur e s .J o ur na lo fc hi l da nda do l e s c e nt p s yc ho p ha r ma c o l o gy.2 0 1 1 ; 2 1 ( 1 ) : 4 3 -5 0 9 .Pf i z e r Ca n a d aI n c . .PRODUCT MONOGRAPH

Pr ARI CEPT®( donepe z i lhydr oc hl or i de ) Ta b l e t s5a nd1 0mgPr ARI CEPT RDTTM ( do ne p e z i lhydr o c hl o r i de )Ra p i dl yDi s i nt e - gr a t i n gTa b l e t s5a n d1 0mgCh o l i n e s t e r a s e I nhi bi t or .FDA Submi s s i onCont r olNo:

1 0 7 2 0 7 .2 0 0 7

1 0 .DunnNR,Pe a r c eGL,Sha ki rSA.Ad ve r s e e f f e c t sa s s o c i a t e dwi t ht h eu s eo fd o ne p e z i l i nge ne r a lp r a c t i c ei nEngl a nd.J o ur na lo f p s y c h o p h a r ma c o l o gy( Oxf o r d ,En gl a n d ) .2 0 0 0 ; 1 4 ( 4 ) : 4 0 6 -4 0 8

1 1 .Be na z z iF.Ma n i aa s s o c i a t e dwi t hd o n e p e z i l . J o u r n a lo fp s yc h i a t r y& n e u r o s c i e n c e:J PN.

1 9 9 9 ; 2 4 ( 5 ) : 4 6 8 -4 6 9

1 2 .Ume ga k iH,I t o hA,Suz ukiY,Na be s hi ma

T.Di s c o nt i nuat i o n o fdo ne pe z i lf ort he

t r e a t me n to fAl z h e i me r ’ sd i s e a s ei nge r i a t r i c

p r a c t i c e .I n t e r na t i o na lp s y c h o ge r i a t r i c s/I PA.

2 0 0 8 ; 2 0 ( 4 ) : 8 0 0 -8 0 6

1 3 .Lo c kha r tI A,Mi t c he l lSA,Ke l l yS.Sa f e t y a ndt o l e r a bi l i t yo fdo ne p e z i l ,r i va s t i gmi ne a ndgal a nt ami nef orpa t i e nt swi t hAl z - he i me r ’ sd i s e a s e :s ys t e ma t i cr e vi e w o ft he

‘ r e a l - wo r l d ’e vi d e n c e .De me n t i aa n dge r i a t r i c c o gn i t i ved i s o r d e r s .2 0 0 9 ; 2 8 ( 5 ) : 3 8 9 -4 0 3 1 4 .Ti s e oPJ ,Pe r d o moCA,Fr i e d h o f fLT.Co n -

c ur r e nta d mi n i s t r a t i o no fd o ne p e z i lHCla nd c i me t i di ne :a s s e s s me nto fp ha r ma c o ki ne t i c c h a n ge sf o l l o wi n gs i n gl ea n dmu l t i p l ed o s e s . Br i t i s hj our na lofc l i ni c a lpha r ma c o l o gy.

1 9 9 8 ; 4 6Sup p l1 : 2 5 -2 9

1 5 .Ti s e o PJ ,Pe r domo CA,Fr i e dhof fLT.

Co n c ur r e nta d mi ni s t r a t i o no fd o ne p e z i lHCl a ndke t o c o na z o l e :a s s e s s me nto fp ha r ma - c oki ne t i cc hange sf ol l owi ng s i ngl eand mul t i pl edo s e s .Br i t i s hj o ur na lofc l i ni c a l p ha r ma c o l o gy.1 9 9 8 ; 4 6Sup p l1 : 3 0 -3 4 1 6 .Ya s u i -Fu r uko r iN,Fur uk o r iH,Ka ne d aA,

Kane ko S,Ta t e i s hiT.The e f f e c t sof Gi nkgobi l o bae xt r a c t so nt hepha r ma c o k i n e t i c sa n dp h a r ma c o d yn a mi c so fd o n e p e z i l . J o u r na lo fc l i n i c a lp h a r ma c o l o gy .2 0 0 4 ; 4 4 ( 5 ) : 5 3 8 -5 4 2

1 7 .Ti s e oPJ ,Per domoCA,Fr i e dhof fLT.

Co n c ur r e nta d mi ni s t r a t i o no fd o ne p e z i lHCl a nd di goxi n:a s s e s s me ntofpha r mac o - ki ne t i cc ha nge s .Br i t i s hj o ur na lo fc l i ni c a l p ha r ma c o l o gy.1 9 9 8 ; 4 6Sup p l1 : 4 0 -4 4 1 8 .Ti s e oPJ ,Fo l e yK,Fr i e dhof fLT.Co n-

c ur r e nta d mi n i s t r a t i o no fd o ne p e z i lHCla nd t h e o p hyl l i n e :a s s e s s me n to fp h a r ma c o k i n e t i c c ha nge sf o l l o wi ngmul t i p l e -do s ea dmi ni s - t r a t i o ni nh e a l t h yvo l u n t e e r s .Br i t i s hj o ur n a l o fc l i ni c a lp ha r ma c o l o gy.1 9 9 8 ; 4 6Sup pl1 : 3 5 -3 9

1 9 .Ti s e o PJ ,Fol e y K,Fr i e dho f fLT.The e f f e c to fmu l t i p l ed o s e so fd o n e p e z i lHClo n t hep ha r ma c o ki ne t i ca ndp ha r ma c o d yna mi c pr of i l eofwar f ar i n.Br i t i sh j our nalof c l i ni c alphar mac ol ogy.1 99 8; 46Suppl1 : 4 5 -5 0

2 0 .Ki m YH,Ba eMJ .Th ee f f e c to fKo n gJ i n Da no nt hel i pi dme t a bo l i s m i nr a t sf e d hi ghf a t -di e t .JEa s t -We s tMe d.2 0 0 1 ; 1 4 : 6 1 -7 8

2 1 .Ki m YS,Le eJ D,Ki m CH,Cho iDY,Pa r k DS,Nam SS,KangSK.TheEf f e c tof Go n gj i nd a nAq ua -a c up u n c t u r eo nt h eCD4 + T c e l lc o unta ta l .i nr a t swe r ea dmi ni - s t e r e dwi t hMTX.JKo r e a nAc upMoxi So c .1 9 9 9 ; 1 6 : 1 7 9 -2 0 2

2 2 .Cho iKH,Pa r k CS.An a na l ys i so ft he Go ngj i nda n’ si ngr e di e nt sa ndi t se f f i c a c y o na n t i -o xi d a t i o n.Ko r e aJHe r b o l o gy.2 0 0 7 ; 2 2 ( 2 ) : 5 1 -6 3

2 3 .Se o ngKM,Ha eRK,So ngBK.Th ee f f e c t o fGo n gj i n - d a no ngl i o s i si nmi d d l ec e r e b r a l ar t e r yoc c l us i on( MCAO)r at s .JKor e a Or i e n t a lI n tMe d .2 0 0 9 ; 3 0 : 6 7 4 -6 8 4

2 4 .Hwa ng SM,Chung DK.TheEf f e c t so f KongJ i n-Da n( KJ D)ont heAl z he i me r ’ s d i s e a s emo d e li n d uc e db yCT1 0 5 .JOr i e n t a l Ne u r o p s yc hi a t r y.2 0 0 4 ; 1 5 ( 2 ) : 1 0 3 -1 1 8

2 5 .J un gHC,J a n gHJ ,Su n gWY,Le eSH,So n J H,Ha nSH.A s t udyo fGo ngj i n-da ni n p a t i e nt swi t hmi l dde me nt i ao fAl z he i me r t yp e .JOr i e nt a lNe ur o p s yc h i a t r y.2 0 0 4 ; 1 5 ( 2 ) : 1 4 1 -1 4 8

2 6 .Pa r kMY,Ki m J D,KuSK.Si ngl eOr a l

Do s eTo xi c i t yTe s to fKo ng-J i n-Da n,a

Po l yhe r ba lFo r mul ai nI CR Mi c e .Bi o mo -

l e c u l e s& The r a p e ut i c s .2 0 0 7 ; 1 5 ( 4 ) : 2 4 5 -2 5 1

2 7 .Le eSN,Pa r k J H,Ku SK.Mi c r o nuc l e us

Te s to fKo ng-J i n-Da n,aPo l yhe r b a lFo r - mul a ,i nBo neMa r r o w Ce l l so fMa l eI CR Mi c e .To xi c o l o gi c a lRe s e a r c h.2 0 0 8 ; 2 4 ( 3 ) : 2 1 3 -2 1 8

2 8 .Ch ung DK,Kwo nOD,Pa r kSJ ,Le eYJ , KuSK.Ef f e c to fGo n gj i nd a n,aTr a d i t i o na l Ko r e a nPo l yh e r b a lFo r mul ao nt h ePh a r ma - c oki ne t i c sPr o f i l e sofDone pe z i li nMa l e SD Ra t s( 1 ) .Kor e a nJ o ur na lofOr i e nt a l Pr e ve nt i veMe d i c a lSo c i e t y.2 0 1 3 : 1 7 ( 1 ) : 7 7 - 8 8 .

2 9 .Gi ba l diM,Pe r r i e rD.Pha r ma c o ki ne t i c s . 2 n de d .Ne w Yo r k :Ma r c e l -De k ke r ;1 9 8 2 . 3 0 .Ch i o uWL.Cr i t i c a le v a l u a t i o no ft h ep o t e n t i a l

e r r o ri npha r ma c o ki ne t i cs t udi e so fus i ng t hel i ne a rt r a pe z o i da lr ul eme t ho df o rt he c a l c ul a t i ono ft hea r e aunde rt hepl a s ma l e ve l - t i mec u r ve .J o u r na lo fp h a r ma c o k i ne t i c s a ndbi o p ha r ma c e ut i c s .1 9 7 8 ; 6 ( 6 ) : 5 3 9 -5 4 6 3 1 .Fo xJ G,Co he nBJ ,Lo e w FM.La bo r a t o r y

a ni ma lme d i c i n e .Or l a nd o :Ac a d e mi cPr e s s I n c . ;1 9 8 4 .

3 2 .Ta j i maY.Bi o l o gi c a lr e f e r e nc ed a t abo o k o ne xp e r i me nt a la ni ma l s .Ta j i maY,e d i t o r . To k yo :So f tSc i e nc eI nc . ;1 9 8 9 .

3 3 .Di c ki nson BD.UHC dr ug monogr aph:

Do ne p e z i l .UHC( Uni ve r s i t yHe a l t hSys t e m Co ns o r t i u m)Se r vi c e sCo r p o r a t i o n .1 9 9 6 : 1 -1 4 3 4 .Mi h a r aM,Oh n i s h iA,To mo n oY,Ha s e ga wa J ,Shi ma mur aY,Ya ma z a kiK,Mo r i s hi t a N.Phar macoki net i csofE2020,ane w c ompound f orAl z hei me r ’ sdi s eas e,i n h e a l t h yma l ev o l u n t e e r s .I n t e r n a t i o n a lj o u r n a l

o fc l i n i c a lp h a r ma c o l o gy ,t h e r a p y,a n dt o xi - c o l o gy.1 9 9 3 ; 3 1 ( 5 ) : 2 2 3 -2 2 9

3 5 .Ti s e oPJ ,Ro ge r sSL,Fr i e d ho f fLT.Ph a r - ma c o ki ne t i ca ndpha r ma c o dyna mi cp r o f i l e o fdo ne p e z i lHClf o l l o wi nge ve ni nga dmi - ni s t r a t i o n.Br i t i s hj o ur na lo fc l i ni c a lp ha r - ma c o l o gy.1 9 9 8 ; 4 6Su p p l1 : 1 3 -1 8

3 6 .Ti s e oPJ ,Pe r d o moCA,Fr i e d h o f fLT.Me t a - bo l i s m a n de l i mi na t i o no f1 4 C-d o ne p e z i li n he a l t hyvol unt e e r s :as i ngl e -dos es t udy.

Br i t i s hj our na lo fc l i ni c alpha r mac o l ogy.

1 9 9 8 ; 4 6Sup p l1 : 1 9 -2 4

3 7 .Roge r sSL,Fr i edhof fLT.Long-t er m e f f i c a c ya n ds a f e t yo fd o n e p e z i li nt h et r e a - t me nto fAl z he i me r ’ sdi s e a s e :a ni nt e r i m a na l ys i so ft her e s ul t so faUSmul t i c e nt r e o p e nl a b e le xt e n s i o ns t u d y.Eu r o p e a nn e u r o - ps yc ho pha r ma c o l o gy:t hej o ur na lo ft he Eu r o p e a nCo l l e g eo fNe u r o p s y c h o p h a r ma c o l o gy . 1 9 9 8 ; 8 ( 1 ) : 6 7 -7 5

3 8 .Ma t s uiK,Mi s hi maM,Na ga iY,Yu z ur i ha T,Yo s hi mur aT.Abs o r p t i o n,di s t r i but i o n, me t abol i s m,ande xc r e t i onofdone pe z i l ( Ar i c e p t )a f t e ras i ngl eo r a la d mi ni s t r a t i o n t oRa t .Dr ugme t a bo l i s m a nddi s p o s i t i o n:

t h eb i o l o gi c a lf a t eo fc h e mi c a l s .1 9 9 9 ; 2 7 ( 1 2 ) : 1 4 0 6 -1 4 1 4

3 9 .Ti s e oPJ ,Va r ga sR,Pe r d o moCA,Fr i e d h o f f

LT.Ane va l u a t i o no ft hep h a r ma c o k i n e t i c s

o fd o ne p e z i lHCli np a t i e nt swi t hi mp a i r e d

he p a t i cf un c t i o n.Br i t i s hj o ur na lo fc l i n i c a l

p h a r ma c o l o gy.1 9 9 8 ; 4 6Sup p l1 : 5 1 -5 5