Exptl Eye Res. ( 1966 ) 5 , 1 9 1 - 1 9 7

U p t a k e and Di s tr ibut ion o f C h l o r p r o m a z i n e in A n i m a l E y e s *

l-lARRY GRVlEN AND TH~._=ODOR~ ]~LLISON

,Smith Klin.e and .French Laboratories, tnc . , Philadelphia, Pennsyl.(:a~zia, U.,S'.A.

(Received 22 A:ove.mber 1965)

[3~S]Chlori)romazin(; was orally admin i s te red dai ly to dogs for periods up to 4 weeks. Considen~ble a m o u n t s of labelad mater ia l were present, iJt the uvea.1 t issue af ter the first week. and the coneent,ra tit))~ rea('hed ~ m a x i m u m a.t the end of t~he th i rd week. ,'No de t ec t ab le lab~;led m~xt t, ria.1 was found ei ther in the cornea or lens af ter 4 weeks, and only t.ra.¢'e r~,nounts ~e rc de tec ted in the anter ior aqueous }tu))lOr. T h e r0)il.ity of tim u r e a to u~ke up the d rug af ter i n t r avenous administrr~tion was d<:pressed by ,)~-5 °-',,o Mter oral pret.reut.ment xvit.h noll- radioaetiw~ drug fl)r 3 weeks.

Similar sturkies with p igmen ted and albino r~l)bits showed t h a t the labeled materiM ae(:umuln.ted only in tim pigu.mllted uvca. ~laxi)nun~ [uvels of ~ecumuh~tio:x were attM~ted a l ter 3 weeks, and then the concent ra t ion thH S0u:f) to "t s t eady- s t a t e level, wlfich was main. rained for the du ra t ion o f H,,,' expor iments . No de tec tab le labeled mater ial was foutt([ i~t the cornea, lens, or aqucons humor of t, hc anter ior ch.~mber. ])iseontimm.tio)t o f the drug a f t e r lhe l.hirrl week resul ted in n. slow c]isapl.)uaranec of ]a.be|ed ma.terial from the u rea . W h e n no))hfl.)t:ied (~rug wtts ad)niniste:red ,'tiler the l.hivd week. rapid exchange o f the htheJed material in the urea) oeeurrt:d. The lal)eled rnateria.l in a.ll exl)er.ituent~ was separatc~l into two pools, o))e eont~)ining the drug thr~t, was ex t rac ted a.t p H 8-4. wi lh e thyl a.cotato omd ~he other oontaining the drug thac was no t extracta.b/e ~'.'~". ~:. ,:;.i.'.. ; v'.,::.t;i.aL~...

1. I m r o d u e t i o u

O c u l a r c h a n g e s ( a c c o m p a n i e d or not b v oveT.~c -"" ..-,, m p igmenta t : io r~ ) h a v e bee)L nor.ed i n s o m e long-l:errn. p s y c h i a t r i c , par, i e u t s (Gre in ( : r a n d B e r r y , i 96 , t ; D e L o n g , P o l e y a n d M c F a r h m e , t .965). T h e y h a v e o c . c a r r e d i~l )c)t..b. m a l e a.)ld f e m a l e p a t i e n t s , t a k i n g s u b - sta.nt>Ja.l d o s e s o f c M o r p r o m a z i n e [ 2 - c h l o r o - l . 0 - ( 3 - d i m e t . h ] . a m i ) o p r g p y l ) - p h e n o t h i a z i n e ] f o r 2 y e a r s o:..- m o r e . T h e oc.uh~r c h a n g e s r e p o r t e . d c o n s i s t o f t h e d e p o s i t i o n r.)f f ine: dot... l ike p a r t i c l e s in t h e a n t e r i o r c a p s u l a r a l td s t t b e a p s t t l a r p o r t J o n a o f t h e l e n s ~;)~ t h e p u p i l l a r y a r e a a n d , l e ss f r eq t t en t ,}y , in. t h e , .x)rnea, c h i e f l y i n t h e p o s t e r i o r l a y e r , t : t .more a d v a m ~ e d c a s e s , s t a r - s h ~ q ) e d opac i t . i e s h a v e b e e n o b s e r v e d in t h e a n t e r i o r c a p - s / f l a t p o r t i o n o f t h e l ens . ~Pbe n a t , u r e o f t h e p a r t i c l e s f o u n d in t h e e y e s h a s n o t y e t b e e n d e t e r m i n e d , n o r h t t s d i r e c t in t e ra t~ t ion o f t h e d r , zg o r i t s maraboU_ires w i t h t h e s c in t t a , - o e u l a r t i s s u e s b e e n f ea r ed , l~a.rl ier s t u d i e s b y }~ot ts (1962) s h o w e d tha t . t h e r a b b i t u v e a l tl~aeg s e l e e l ) i v e l y s t o r e d N - s u b s t i t u t e d p h e n o t t d a z i n e s af t .e r i n t r a v e n o u s h t j e e t i o n a n d t h a t u v e a l } ? i g n n e n t a t i o n w a s a p r i m a r y f a c t o r ia~ bhis s t o r a g e .

lo , - ' ~ T h e p r e s e n t sr, u d y w i t h d o g s a n d r a b b i t s a t t e m p t e t ~ ", ': . . . . -,~y t h e m e c h a n i s m r e s p o n s i b l e f o r t h e s e o c u l a r c h a n g e s .

2. M a t e r i a l s and M e t h o d s Rabbits

M a l e a n d fema.Ie r a b b i ~ of t h e ' N e w Z e a l a n d w h i t e (a lb ino) s t r a i n ant! o f t h e ]3elgi~n H a r e ( p i g m e n t e d ) s t r a i n , w e i g h i n g 1-6-9-4 kg, w e r e used . In gene ra l , t h e m a l e s w e r e heavier t h a n t h e f e m a l e s .

* Presented at the ~Ieeting of the A~ociation for Resea.rch in OphbhMmo|ogy, ~'cw York, 2~ JunB I965.

191

192 HARtCY G R E E N AND T H E O D O R E E L L I S O N

3 5 Capsu les were p r e p a r e d f r o m a m i x t u r e o f [ • S ]ch io rp romaz inc - ] i [CI a n d tact.est, so t h a t e ach capsu le c m z t a i n e 4 85 m g of r a d i o a c t i v e d r u g w i t h a SlmCiac a c t i v i t y of 0.26:3 Hci"mg. T h e d o s a g e r e g i m e n was o~e ca.l~sule t)cr r a b b i t pet" day , m:hnin is te red in t.hc m o r n i n g by m e a n s of a v e t e r i n a r y ba.lling gun . A t t h e s t m ~ of the exT)erimmtt., e'.~ch , 'abbi~ receive, l a b o u t :2.2 izo of t.he rmtioa.et ive (b.atg. Tim ~ tmmmt a d m i n i s t e r e d dec reased wi th t).te progress o f t h e e x p e r i m e ~ t because of t h e spontaneou-u rad ' ioact ive decay (half- l ife of 87 days) . T h e dnZ.a r e p o r t e d have bcetx cor recged for th i s decay .

T h e fo l lowing p r o c e d u r e s wer~.~ used irt t h e e x p e r i m e n t s .

Proced.~re 1. [a~S]Ch]orpromnzine was ora l ly a d m i n i s t e r e d (l~li])- [})r 8 weeks to ma le p l g m e n t c 4 rabb i t s . One rabbi~ was .kille.,:l a f t e r t.he ill 'st saul s econd weeks a n d ~wo a f t e r euc}~ of t h e ~tcxt 6 weeks . Th is p r o c e d u r e wa.s a.lso ca r : i ed out. on female t)ig, n e n t e d rabb i t s a n d o~t mu le a n d f e m a l e a lb ino r abb i t s .

~roccrh~re 2. [ ' ~ S ] C h l o r p r o m a z i , m wa.s or; t l lv a d m i n i s t e r e d da i ly for 3 weeks l:o nmte p i g m e n t e d rabb i t s , followec[ by no d r u g ~ re ; t tmen t (h i r ing the n e x t 4- weeks . Tw,) r abb i t s we.re ki l led each w e e k a f t e r t h e t l t i rd week.

Proeed~2.re .'3. [ ° sS ]ChIo rp romaz i~e was ,~ratlv a d m i n i s t e r e d cI:-;i;v for :] weeks to re:tie p i g m e n t e d r~bl)its, fo l lowed b~-administ .ra*,io~ of n(m, 'ad i (met ive (.Ir~g o~dy at. t he s ame dosage for t i le a e x t ;:, weeks . T w o rabbit.s were k i l led e.'~.eh week a f t e r t he ~}tird week.

ikll r a b b i t s were kil led. 2:1 h r :tl'ter t.he last. (lo~c, by the i~t t ravenous admh~ist.rak.ion of Eut, hot ( N o r d e n Gabs, L inco]u , Nebr. ; (.-oatai~m s o d i u m A'-amyl e thy l a n d s o d i u m ethyl - I - met .hyl b a r b i t u r a t e ) . T h e ~q.ucous }tu n o r was ,'etm.}vecl ~'r[)Ilt t he avteri .or (:h:amb(~r immed.- iate.ly a.fter t he d e a t h of the anim'.tl wi th a 27-gau.ge needle f i t ted to a. L-ml sy r i age . The. b.,.ns and t i s sue f r o m t h e iris a n d c i l iary b e d N we.r(~ ca re fu l ly d i s sec t ed and r e m o v e d t h r o u g h t h e pos t e r io r end of t h e eve. The sc/e.rM t issue of tit(', corne.a was i.~i,,aed i tat on :~ co rk b o a r d a~ld t, he corneal t)utmhe.d our, roy mea~ts of a, t r e p h i n e or c i rcu lar pu~lch.

Extractio;,. el" drug f r o m eye tissue All e x t r a c t i o n s were p e r h ) r m c d izl 4ira l igh t and izl Low Act in ic glass boa.tics p r e p a r e d

in t h e glass shop of S m i t h K l i n e & Fre~tch L a b o r a t o r i e s . E a c h t i ssue was rittsed w i t h sal ine, b lo t t ed t igh t ly wi th fi l ter pape r , we ighed , c u t in to sinai! pieces, and placerl izl 14-ml s c r e w - c a p vials, to wh ich were a d d e d 2-0 ml of 0.1 ~" NaOI~ ~nd 0. I n:d of" 5~/o N~a~SOa. E a c h vial was f lushed w i t h No gas, t&e sc r ew-cap t i gh te lmd , a n d t h e whole h e a t e d ia a bo i l ing w ' t t e r b a t h for 1 hr . T h e vials were t h e n cooled and t h e center , re a .d jus te4 to p H 8-4 w i t h I N H01 ( a b o u t 5 d rops) a n d e x t r a c t e d twice , w i t h s h a k i n g for 10 mi n, ~ / t h 6-0-ml portiolLs o f w a t o r - s a t u r ~ , e d e t h y l ace ta t e . A 3-ml a l iquo t , in d u p l i c a t e , of t h e e t h y l acetaLc ext rac~ was p ipe t~ed i n to l i qu id sc i~ t i l la t ior t vials and t h e voil~me r e d u c e d to 1 ml b y evapo rav ion ia a s t r e a m of Ne gas. Aqueous p h o s p h o r (15 nxI) ~'as ~dded a n d the r~dio- ~c t i v i t y c o u n t e d in ~ P a c k a r d q~ri-Carb l iqu id sci t~ti]latioa s p e c t r o m e t e r .

The aq t teous layer of t h e e t h y l a c e t a t e ex t rac~ c o n t M n e 4 s u s p e n d e d ma te r i a l . Th i s w,~Ls m i x e d tho roug] f ly in o rd e r to ach i eve a ma i fo rm d i spers ion . A. 0 .1 -ml a l iquo t , in dup i iga t e , was t h o r o u g h l y m i x e d ~ d t h 15 ml of a q u e o u s p h o s p h o r [a. solu~iort i,~ a b s o l u t e e t h a n o l c o n t a i n i n g 5Or rig 2 .2 -p tmny leneb i s (5 -pheny loxazo le ) , 7 g 2,5-diphenyl.oxazole~ 8 0 g naph t lu~ lene , 400 ml t o Iuene , 400 m g p-d ioxa l t e , in ,~ f i na l v o l u m e o f 100 ml , to w h i c h is a d d e d 4-6°/o Cab-o-siI (Godf rey -L . Cabo~, Inc . , Bosto~l, Mass . ] in ~ l iqu id sc ia t i l i a t ion via.[ and vhe r a d i o a c t i v i t y counted. Thisva. lue is referred ~o as t i le ra.dioact[vi~y of t h e no,x- e x t r a c t a b l e or res idu~i f r ac t ion . T h e a q u e o u s hmnoua- was m i x e d d i r e c t l y w i t h t h e a q u e o u s p h o s p h o r a n d ~he .cadAoac~i~-ity counted.

:Foul" groups of one rnMe and ou~ female pure-bred beagle dogs (average weight, tO kg) were given the drug in capsule form daily for periods up to 4 weeks. Each dog received

1 . ? : P T A K l g , 7 D I S T R I B U T I O N OI," C l t ] . O I ' ~ P R O M A Z I N E 1.9{i

10/ ,c of [a~S]chlorpromazine in a to ta l dose of 20 mg/kg . 0 n o g,'ou I, was ki]~led a t ~he end of each week, 24 hr a f te r the last dose, and the ,::.yes processed as desc r ibed for rabbi t s . Af te r alkal ine d iges t ion for ] h r a t 100°C.. t he resu l t ing solut.ion wa.s d i lu ted with dist, iHed w a t e r and an a l i quo t c o u n t e d frn- r ad ioac t iv i ty .

All c o n c e n t r a t i o n s m'e expressed in t e rms of chh)rpront; tzine coute, n t pe, r g ram of tisstte and are base,:t izpon t.he amount , of radioactive, (Irug present . The vnlues were cor, 'ecte(l for que.nch. N o cons i s t en t diff-.fence in radioa( : t iv i ty concerttratiot~ was observed betwemt the. tissues from left a u d right, eyes; the re fore , all va lues are uverages of bo th tissues fl 'om each animul or of bo th t issues f rom all t.hc an imnls in each group.

3. Resu l t s Dogs

T h e resxtlt.s o f t h e da i ly , oral a d m i n i s t r a t i o n of labcqcd d r u g a r e s h o w n in T a b l e I . C o n s i d e r a b l e al/Toutlts~ o f r a d i o a c t i v e m a t e r i a l we re feared ial t h e uve,~ a f t e r t h e f irst week . a n d t h e c o n t e n t . r a t i o n r e a c h e d a. n~axin~l,l~ at. t h e e~ct of t h e t h i r d w e e k . At Lhe (.,n(l of t h e fom-th we, ek , t h e c o n c m d rat ion w a s s l i g h t l y lower .

TA]II . P. I

Chlort.,roma=i'~e cor~cen.tra~.io;z in. tim uve, t..~ of dogs after daiiff orcd administragiou *

' h lo rp ro ma z inc ' ] ' ren t I t le r l C CO neetlLr~t bion

(weeks ) (~ ~"el ~.

2S0~ 2 346 :~ 419 4 3,S~.~

* ~C~mh p u r e . b r e d beagle (aver.age we igh t , I0 kg) r ece ived t lai[y 10/~c n!' [aa,~.]e |f iorpromazine (spe.eific aegivit.y. ~t ~xC/mg} in a re,tel d~.,se o1" 20 mg/kg .

+ Vahms ave a v e r a g e s of t he trJt.al radhmet. ivi t .y of t he uvea.~ I'rom title nm]e a n d <~lle ,tema|u dog exjove~sed as e~,ncent.rat..iorl g~f c~hh.~rpr~;mnzine in blm t i ssne . Avocet( : we t w e i g h t o f 16 t i ssues -5:a::" 331 rag.2 ~g.

No labe led n~ator ia l w a s f o u n d i n e i t h e r t im cornea, o r t ens a f t e r 4 w e e k s of d r u g a dminist ,r , ' t t ion, a n d o n l y t r a c e a n t o t m c s w e r e d e t e c t a b l e in t h e a q u e o u s h u m o r . As I.it.rle as 0-15/~g of l a b e l e d m a t e r i a l cou ld t.m rel ia .My m e a s u r e d .

i n a. s e p a r a t e CXlx;riment., i t w a s f o u n d t h a t t he a b i l i t y of t h e ux 'ea to t a k e u p t h e d rug a f t e r i n t r q v e n o t m a d m i n i s t . r a t i o n w~,.s d e p r e s s e d a b o u t 550/0 a f t e r era.1 p rc t . r~ . t - m e a t w i t h n o n r a d i o a c t i v e d r u g . One m a l e p u r e - b r e d b e a g l e (9 kg) was g i v e n c h i e f p r o m a z i n e ora. l ly (20 m g / k g ) d a i l y f o r 3 w e e k s . T w e n t y - f o u r h o u r s a f t e r t h e l a s t dose , 10 m g o f [ a '~S]ch lo rp romaz ine (specif ic a etix~it) :, 4 b~c/mg) w a s i l t j e c t e d i n t r a v e n o u s l y . Anotl~er i n a l e dog , nob p r e ~ r e a t e d w i t h t-he m f l a b e l e d ( h u g , r e c e i v e d a n e q u a l dose of [ a~S]eh lo rp romaz ine a n d s e r v e d as a c o n t r o l . B o t h dogs we re k i l l e d 15 nil,1 a f t e r inject.imp. T h e a v e r a g e tote.1 r a d i o a c t i v i t y of t h e uv,.,as o f b o t h eyes , e x p r e s s e d a.s ~tg of c h t o r p r o m a z i n e p e r g r a m of t i sane , was: c o n t r o l , 3-21; a n d e x p e r i m e n t . e l , 1-4:3.

Male l~q~r,e~led rabbits

T ~ e a t m e n t a c c o r d i n g t o Procedure 1 r e s l t t t ed in a m a r k e d u p t a k e o f t h e d r u g d u r i n g the f irst w e e k , a n d t h e c o n c e n t r a t i m x i n c r e a s e d d u r i n g t h e s e c o n d w e e k to a m a x i m l u n

t94 H A R R Y G I { E E N A N D T H E O D O R E E L J D 1 S O N

of 734/~g/g. Durlng the third week, the concentrat ion decreased by about 80°//0 ~o 14,1. #g/g and remained ra ther constant dttring the last 5 wee, ks of the expcrimm~t. During the first. 2 weeks, the eoa(:entratioJ~ of the dmtg in the cxr, ract was about. 63~/o of the to ta l dza~g concentra t ion in the tissue. Howc~ver, t[~e marked (tcc,:ease i~ t h e total drug conccn~n~tion during the tMrcl wee~~ was characterized b)" a. much greater

8 O O

4 0 0 o ~ , : 4

~" P-00

,&, l

.~_ f O 0

4 0 C.I

_ _ . _ .

~O. -

I 2 5 4 5 6 "g 8

T:me (weeks)

I -! - i

i

. . . . J

FI(:;. I. Cldorpromazinc (:oP.ct;ntrat, iozt in the uw;al tissue of male pigmented rabbi ts (Yro~'ed.,re 1, sc~; text).

0h lorpromazine r ormentrat ioa, bused upon |ttaourtb of radioact iv i ty preseng, i~ ~otal tisstm ( O - Q - Q ) , in e thyl acegate ext.racg (.pH: 8-4; ~ : - ~ - . ~ ). and in re.~idue ( ~ - ~ - ~ , ) .

decrease of the drug concentr~tion in the extract than in the residue: so that , aB the cud o:f this period, the resulting drug concentrat imt ilz t..he ex-tra.ct was about 30 °` ̀ of" the

" , ' O

totM. No fur ther significant change in dis t r ibut ion occ ma'cd thereafter (Fig. 1).

200

100~

-- ~0 -

P .~ e o -

{0 i I

• : ?" .

2 3 4 5 6 7

T ime (weeks)

1 J

- i

.oA

8

~'rc, 2. Qhlorpromazine coaeenbration in the uveM tissue of r~mle p igmen ted rabbi~s (Proced~tre2, see ~ex~}.

Chlorproma.zino concentra t ion, based upon a u m u n t ofz, adioa.oti~dty present, in f~o(~al tissue.f~-[:3-~-"q), i~ etb.yl ace ta te ex t rac t (pH 8-4; ~ - ~ , - ~ ) , and hx reniduo ( ~ - ¢ 7 / ) . Arrow indicates the cessabior~ of chior.promazinc t rea tment .

Trea tmen t according to P.rocedure 2 resulted in no apparen~ change i~1 the concen- t ra t ion of . the drug i n the u r ea during l~he first week after t r e a tmen t was stopped. During the nex t 3 weeks, however, the concentra t ion felt a t a fah'Iy cons tant ra te to

U P T A K E , I ) I S T 1 R I B U T I O N O 1 ~ C H L O R P r g o ~ I A Z I N E 1 9 5

4.3/~g/g, a toSal decrease of 76°fo..4dt, hough the Corm drug eoneentra~,ioa ia the urea remained unchanged during the first week after drug trea.tm.ent was stopped, rcdistr ibutioa of the drug begwem~ the two pools occurred. The coneehtr.ttio~ of the drug in the residue decreased wi~h a correspond ingincrease of dn~g concentration in the extr~tet.. Dur ing the next 2 weeks, however, when tl~e cm~centration of the drug in the extract decreased by Mmost 90~/o, tile drug concentrat ion in the residue decreased by only I6~/o. A_ reverse si tuation was observed durh~g the last week, when the concen- tration of the drug in the residae decreased by almost 60~/o, while tha t izt tim ext rac t increased s l ight ly (Fig. 2).

c~

0

L )

. . . . ' ~ T ~ , i

~ 0 0 _-

4 0 - -

1 0 : :

- l 4 "- I ~.

: ( ~ = ! ! • 2 3 zi 5 g Z 8

Time ('-ee e ks)

l " I c . 3. C k l o r p r o m a z i n e c o n c e n t r - l t i o n i n t h e a r e a l t . i s sne n f r o m e p i g m e n t e d r a b b i t s (~Orocedure J, .qeo te.~t).

C ' h l c~ , ' p romaz ine c t m c e n t r a . t i o n , b a s e d u p o n a l n m m ~ o f r a d i o a c b i v i t y p r e s e n t , i n t o S a l t i s s u e ( /~ - ~ - A ), in e t h y l aect,~.~e e x ~ r a r . t (p-t{ 8-4: ~ . - 2 X - A ) , a n d in re .~ idue ( g a - ~ ) . A r r o w i n d i c a t e s t .he b e g i n n i n g o f t h e t r e . ~ t r n e n t w i t h i m l a b e l e d c h l o r p r o m a z i n e .

Treatraent according to Procedu.re 3 resulted in. a 69~/o decrease of the conceutrat ion of the labeled materia.1 in the u~-ea by the end of the first week of t r ea tment with the unlabeled drug. The concentrat ion decreased less markedly during the next week to a level t ha t was ra ther constant during the rema.i.nhlg 3 weeks. (T. hese values w-ere b,sed upon t, be concentratiort of labeled drug remaining in the uvca.) Tl,e observed decrease iu to ta l drug concentrat ion was accompanied by simultaneous decreases, at. about the same rate, in the concentrat ions of the dmtg in both pools. N~o sig~ifieant. further change in distr ibution occurred during the remaimng weeks of the exper iment (Fig. 3). The iadicated increase a t vl~e end o£ the fifth week is not significant.

Female pigme.nted rabbits:-

In general, the c h a n g e s i n the total drug concentrat ion in the u r e a of the female pigmented rabb i t an4 ha tl~e distr ibution of ~he drug betwee~ the tWO pools were similar to those described for male pigmented rabbits. The only observable difference in tim responses of the ~wo sexes was in the magni tude of the ut)take of the dnrg and the resulting constant level at tained during the la t ter weeks of r, he adminis t rat ion according to ProciMure 1. The max imum concentrat ion of th.e dn lg h t the uve~ of the female rabbit was 374/ag/g at the end of the second week of treatment,~vhilc t h a t i~ t h e u r e a of the male rabb i t was 73.4/~g/g..During the next 2 weeks, the concentrat ion decreased to ] 22/zg/g and then rose and settle~I betweo.n 250 and 300/~g/g during the last 4 we¢ks.

196 H A R R Y G R E E N A N D ! ] ' t I E O I ) O l l E I ' ] L L I S O N

Non~oiggnented rabbits No measm'able radioaet, iv i ty was fmmd in the uvea~ of ell;her male or female a l bino

ral.~bits following t .reatment according to Proeed.m'e 1.

Agueo~.,s ?~umor, cornea a'nd lens No measurable rad ioac t iv i ty was found in the aqueous humor of the anter ior

chamber, Conies, or ions of any of the rabbi ts trea:t.ed according to the procedures described. Rad ioac t iv i t y equivalent to 0.013-0-025/xg of the drug could bc reliably measm-ed if present.

4. Discuss ion

The results of the present expcrimm~ts confirm and extend the findings of ]>otl:s (1962) t ha t the rabbi t uveal tract, selectively stores N-,substitutcd pheuothiazine.s after an intravcnm~s inject ion and t h a t a r ea l lJ igmentat ion is a pr imary factor in t.his storage. The pigmented uveal t r ac t of d,:,gs w~.s similarl)- c~.pable (~1' storing the drug af ter chronic oral adminis t ra t ion of chlori~romazine.

.Dm-ing the first 2 weeks of t reatn tei~t, the rate of'~cmmmh~tion of tim cc:'mcenr.ratb:n of drug in the ~:~fi)bit uve~ was maxima, l; during the third week. the ommentrat ion decreased 80% to a level tl.mt. remained constant,, qThe sharp decree.so in dmig conu,.,it- t.ru.t.ion dur ing the th i rd week of t rea tn ien t p robab ly reflects llot].i a decreased rai,., <.~1' ltl)t, al~:e o f J r t t g a n d the {brlnatiotl of motabolir , es witt~ r e d u c e d teltOOll.(;V to be s tore, . [ by the t.ismm. ,c'5xtppo,.'t 'for this concepl~js, first,, tim denlonstratio~l t]lat t-hq} al.>ilii:x- of dog urea to take up the drug after int.rare~mus admiJfis trat ion was sup.pressed by t.ll~:~ pr ior dai ly oral adr,finis'c.ra,tioll, of the dmlg f~or 3 ~reeks and, second, the ol)serviition t.tlat, dur ing the third week, a nmol'~ greater decrease of drug couor alratiol~ ocoul'red in the ext-ract +~han in the residue, lgurthemlzore, the main tena~ce of 5:],e constant eoneer.ttration during tim last 5 weeks of the exper iment was d.epeudent upon the continumts adminis t ra t ion of the drug= indicat ing the a t t a i nmen t of a dynamic s teady-s ta te relationsMp between upta.ke amt di~appeararme of the dntg. The s teady state of the to ta l concentrat ion of 1;he drug in the rabbit, u r e a is fur ther characterized by a cons tan t relat ionship of the concentra t ion of the drug in the, residue to t lmt in t:he extrael;..

.q)o wha t ex-tent the drug irt the u r e a represents p,%rent compound or i ts mete b e t ites is not presently known; analysis o:f the tissues to answer this questimz is current ly in progress, i t is reasonable to asmune, however, t}ta.t the ext ract contains parent, eompom~d artd its metabol i tes in a free form, while the residue represents those moleex~lar species t ha t are assoeia.ted with par t icula te cclhtlar material .

The da ta presented in Fig. 2 suggest t.hat, dur ing the first week ~tfter treatment, was discontinued, the drug t h a t disappeared from the residue entered the ext rac t and that , dur ing the next 2 weeks, the d_rug concentra t ion in the ex t rac t decreased markedly, while t h a t in the residue decreased only slightly. The da ta presented in Fig. 3 indies.to t ha t the d~tg" concentra t ion in the u r e a is in a dynamic relat ionship with the drug adminis tered and t h a t the dmlg in both pools in ~he u r e a exchanges a t s imilar rates with ~)he adminis tered drug.

Despi te the marked abi l i ty of the pigmented u r e a to t ake up and store the drug, little, if any, was found irl the anter ior chamber of the rabb i t eye. Fur thermore , the absence of the drug in the aqueous humor of the a lbhm rabb i t eyes suggests t h a t the barr ier between the u r ea and the aqueous humor m a y no t be l~erm.eable to the drug

UPTAKE, :DISTRIBUTION OF CliLORPR, OMAZINI;~ 197

aad its metabolites. In support of this suggestion is tho observati~a tha~, i~l t,w~2 sep,qrat~, experimelxts, no mdioact i~ty w~s fo~h~d in the a.queous humor of albh~

* t , ° r,'~bbit eyes 30 rain after an intravenous injection of 10 ~ : of [3°S]chlorpromazm.e (~ m,-).

A OK N 0 WL I,] D (~ MEN TS

Expert techaica} a~ista~tco was provided by Mr, Louis Gu~;zait, h~', Joseph Lt~..re, Mrs, ,[.~mi(:o Jnmbo aad Miss Carole Kiss.

R.E FE ICLN CE,,

I)eLoug, S. L., l'oley, ]L O. and 3[cFn.rla.nc: J. R.., ,Jr. (1965). A rck. Ophthabt~ol. (Chie,~ffo) 73, {i1 i. (:',rciner, A. C. and Berry, K. ([964). Can. ~[ed. _.t.~oe. J. 9{)~ 603. ['olt:~. A. 5I. (I962). Trans. Am. OpMhalmal. Soe, 60, 51'i.