Antimicrob. Agents Chemother. 1974 Nauta 300 3

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6(3):300. DOI: 10.1128/AAC.6.3.300.

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A N T I M I C R O B I A L A G E N T S AND C H E M O T H E R A P Y , S e p t . 1 9 7 4 , p . 3 0 0 - 3 0 3C o p y r i g h t 1 9 7 4 A m e r i c a n S o c i e t y f o r M i c r o b i o l o g y V o l . 6 , N o . 3P r i n t e d i n U . S . A .

E f f e c t o f P r o b e n e c i d o n t h e A p p a r e n t V o l u m e o f D i s t r i b u t i o na n d E l i m i n a t i o n o f C l o x a c i l l i nERNST H . NAUTA, HERMAN MATTIE, A N D WI M R . 0 . GOSLINGS

D e p a r t m e n t s o f M i c r o b i a l D i s e a s e s a n d C l i n i c a l P h a r m a c o l o g y , U n i v e r s i t y H o s p i t a l , L e i d e n , T h e N e t h e r l a n d sR e c e i v e d f o r p u b l i c a t i o n 6 May 1 9 7 4

A c c o r d i n g t o G i b a l d i e t a l . ( 1 9 6 8 , 1 9 7 0 ) , t h e h i g h e r s e r u m c o n c e n t r a t i o n s o fp e n i c i l l i n s a n d c e p h a l o r i d i n e r e a c h e d a f t e r a d m i n i s t r a t i o n o f p r o b e n e c i d a r e d u en o t o n l y t o s l o w e r r e n a l e l i m i n a t i o n b u t a l s o t o a n a l t e r e d d i s t r i b u t i o n i n t h eb o d y . To d e t e r m i n e w h e t h e r p r o b e n e c i d h a s a d i r e c t e f f e c t o n t h e d i s t r i b u t i o n o fc l o x a c i l l i n , t h e e l i m i n a t i o n a n d d i s t r i b u t i o n o f c l o x a c i l l i n w a s s t u d i e d i n s i xp a t i e n t s , f i v e l a c k i n g k i d n e y f u n c t i o n a n d o n e w i t h a p a r t i a l l y i m p a i r e d r e n a lf u n c t i o n , i n t h e p r e s e n c e o r a b s e n c e o f p r o b e n e c i d . No s i g n i f i c a n t d i f f e r e n c e w a sf o u n d b e t w e e n t h e mean v a l u e s o f t h e v o l u m e o f d i s t r i b u t i o n o f c l o x a c i l l i n w i t ha n d w i t h o u t p r o b e n e c i d ( 1 3 . 0 a n d 1 2 . 6 l i t e r s , r e s p e c t i v e l y ) . T h u s , t h e h y p o t h e s i so f G i b a l d i e t a l . c o u l d n o t b e c o n f i r m e d f o r c l o x a c i l l i n i n p a t i e n t s l a c k i n g k i d n e yf u n c t i o n . I n s p i t e o f t h e a b s e n c e o f k i d n e y f u n c t i o n , t h e v a lu e o f t h e e l i m i n a t i o nr a t e c o n s t a n t w a s s i g n i f i c a n t l y d e c r e a s e d i n t h e p r e s e n c e o f p r o b e n e c i d ( f r o m0 . 3 2 6 t o 0 . 2 6 3 / h ) . T h i s m i g h t b e e x p l a i n e d b y a b l o c k a d e b y p r o b e n e c i d o f t h ee l i m i n a t i o n o f c l o x a c i l l i n b y t h e l i v e r .A c c o r d i n g t o m o s t a u t h o r s 1 , 2 , 1 1 ) , p r o b e n e -c i d a c t s b y i n h i b i t i n g t u b u l a r t r a n s p o r t o fo r g a n i c a c i d s i n t h e k i d n e y . T h e e l e v a t e d s e r u mc o n c e n t r a t i o n s o f p e n i c i l l i n o c c u r r i n g a f t e r a d -m i n i s t r a t i o n o f p r o b e n e c i d w e r e t h e r e f o r e a t -t r i b u t e d t o i n h i b i t i o n o f t u b u l a r s e c r e t i o n .H o w e v e r , i n 1 9 6 8 G i b a l d i a n d S c h w a r t z ( 5 )s t a t e d t h a t p r o b e n e c i d l e a d s n o t o n l y t o ad e c r e a s e i n r e n a l e l i m i n a t i o n b u t a l s o t o ar e d u c t i o n o f t h e a p p a r e n t v o l u m e o f d i s t r i b u -t i o n o f a n u m b e r o f p e n i c i l l i n s a n d c e p h a l o r i -d i n e i n a o n e - c o m p a r t m e n t m o d e l , a n d b o t hm e c h a n i s m s w e r e t h o u g h t t o b e r e s p o n s i b l e f o rt h e h i g h e r s e r u m c o n c e n t r a t i o n s o b s e r v e d d u r -

i n g p r o b e n e c i d a d m i n i s t r a t i o n . T h e a u t h o r s d i dn o t u s e d a t a o f t h e i r o w n , a n d i t may b e a r g u e dt h a t s o m e o f t h e p u b l i s h e d d a t a o f o t h e r s t h a tt h e y u s e d w e r e n o t r e a l l y s u i t a b l e f o r t h e k i n d o fc a l c u l a t i o n s r e q u i r e d t o p r o v e t h e i r p o i n t .I n 1 9 7 0 G i b a l d i e t a l . p u b l i s h e d a s t u d y ( 4 ) o na t w o - c o m p a r t m e n t m o d e l , u s i n g p h a r m a c o k i -n e t i c p a r a m e t e r s o b t a i n e d i n f i v e p a t i e n t s r e -c e i v i n g b e n z y l p e n i c i l l i n b y t h e i n t r a v e n o u sr o u t e . T h e i r r e s u l t s l e d t h e m t o c o n c l u d e t h a tt h e r a t i o b e t w e e n t h e a m o u n t s o f d r u g i n t h ec e n t r a l a n d p e r i p h e r a l c o m p a r t m e n t s w e r ec h a n g e d b y p r o b e n e c i d i n f a v o r o f t h e c e n t r a lc o m p a r t m e n t . T h e o n l y e x p l a n a t i o n t h e y o f -f e r e d f o r t h i s p h e n o m e n o n w a s a p o s s i b l e i n t e r -f e r e n c e o f p r o b e n e c i d w i t h t h e p e n e t r a t i o n o fb e n z y l p e n i c i l l i n i n t o c e r t a i n b o d y c o m p a r t -m e n t s .

B e c a u s e i n o u r o p i n i o n t h e r e s u l t s o b t a i n e db y G i b a l d i e t a l . d i d n o t w a r r a n t t h e i r d i s c o u r -a g e m e n t o f t h e u s e o f p r o b e n e c i d t o g e t h e r w i t hp e n i c i l l i n , w e i n v e s t i g a t e d t h e s p e c i f i c c l a i mt h a t p r o b e n e c i d w o u l d d i r e c t l y i n f l u e n c e t h ev o l u m e o f d i s t r i b u t i o n o f p e n i c i l l i n . F o r t h i sp u r p o s e w e c h o s e p a t i e n t s l a c k i n g k i d n e y f u n c -t i o n , b e c a u s e u n d e r t h i s c o n d i t i o n a n i n d i r e c te f f e c t o n t h e a p p a r e n t v o l u m e o f d i s t r i b u t i o n b yp r o b e n e c i d v i a a r e d u c e d e l i m i n a t i o n i s e x -c l u d e d . T h e p e n i c i l l i n c h o s e n w a s c l o x a c i l l i n ,b e c a u s e we w e r e f a m i l i a r w i t h t h e p h a r m a c o k i -n e t i c s o f t h i s d r u g i n p a t i e n t s w i t h o u t r e n a lf u n c t i o n ( 9 ) .

MATERIALS AND METHODSP a t i e n t s . F i v e p a t i e n t s ( a g e d 1 6 t o 2 9 y e a r s ) o nc h r o n i c i n t e r m i t t e n t h e m o d i a l y s i s a n d o n e p a t i e n t ( 6 5y e a r s o l d ) w i t h a m o d e r a t e l y d i m i n i s h e d r e n a l f u n c -t i o n ( c r e a t i n i n c l e a r a n c e , 2 4 m l / m i n ) w e r e i n c l u d e d i nt h i s i n v e s t i g a t i o n . T h e s t u d y w a s c a r r i e d o u t b e t w e e nh e m o d i a l y s i s p e r i o d s w i t h t h e p a t i e n t s l y i n g i n b e d .A l l f i v e h e m o d i a l y s i s p a t i e n t s h a d u n d e r g o n e a b i l a t -e r a l n e p h r e c t o m y . L i v er f un ct i o n t e s t s w e r e n o r m a l ,a n d n o n e o f t h e p a t i e n t s h a d a n a b n o r m a l b o d yt e m p e r a t u r e .C l o x a c i l l i n a s s a y . C l o x a c i l l i n c o n c e n t r a t i o n s i nt h e s e r u m w e r e m e a s u r e d b y t h e a g a r p l a t e d i f f u s i o nm e t h o d o n p h o s p h a t e p e p t o n e a g a r ( p H 6 . 5 ) w i t hS a r c i n a l u t e a ATCC 9 3 4 1 , a c c o r d i n g t o G r o v e a n dR a n d a l l ( 6 ) w i t h t h e m o d i f i c a t i o n o f M a t t i e e t a l . ( 8 ) .Th e m i n i m a l s e r u m c o n c e n t r a t i o n t h a t c o u l d b ea s s e s s e d a c c u r a t e l y w a s a b o u t 2 . 5 u g / m l . A f t e r c o l l e c -t i o n , a l l s a m p l e s w e r e s t o r e d a t - 2 0 C . D e t e r m i n a -

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F I G . 1 . S e r u m c o n c e n t r a t i o n s ( C ) a n d t h e c a l c u l a t e dv a l u e s f o r A/V d u r i n g a n d a f t e r t e r m i n a t i o n o f ac o n t i n u o u s i n f u s i o n o f c l o x a c i l l i n i n p a t i e n t V w i t h o u ta n d w i t h p r o b e n e c i d a d m i n i s t r a t i o n .t i o n s w e r e p e r f o r m e d w i t h i n a w e e k .A d m i n i s t r a t i o n o f c l o x a c i l l i n . A f t e r a l o a d i n gd o s e o f 1 g , c l o x a c i l l i n ( 1 g o f s o d i u m s a l t [ O r b e n i n ] i nv i a l s f o r p a r e n t e r a l u s e ) was a d m i n i s t e r e d t o f o u r o ft h e p a t i e n t s b y c o n t i n u o u s i n f u s i o n ( F i g . 1 ) . I n t h r e eo f t h e s e p a t i e n t s , w h o w e r e o n h e m o d i a l y s i s , c l o x a c i l -l i n was i n f u s e d a t a r a t e o f 0 . 6 g / h f o r 4 h . F o r t h ef o u r t h p a t i e n t , t h e o n l y one w i t h a p a r t i a l l y d i s t u r b e dk i d n e y f u n c t i o n , t h e c l o x a c i l l i n was i n f u s e d a t a r a t eo f 1 . 2 g / h d u r i n g 3 h . I n t h e o t h e r two p a t i e n t s ,c o n t i n u o u s i n f u s i o n was n o t p o s s i b l e f o r p r a c t i c a lreasons, a n d c l o x a c i l l i n was t h e r e f o r e a d m i n i s t e r e d b ya s i n g l e i n t r a v e n o u s i n j e c t i o n o f 1 g . T h e samep r o c e d u r e was r e p e a t e d d u r i n g a d m i n i s t r a t i o n o fp r o b e n e c i d .A d m i n i s t r a t i o n o f p r o b e n e c i d . T h e d o s e o f pro-

b e n e c i d was n o t a d j u s t e d b e c a u s e t h i s d r u g i s m a i n l ye l i m i n a t e d e x t r a r e n a l l y ( 1 , 2 ) . A d m i n i s t r a t i o n o f 0 . 5 go r a l l y a t 8 - h i n t e r v a l s was s t a r t e d 2 4 h b e f o r e t h ec l o x a c i l l i n was g i v e n .C a l c u l a t i o n s : e l i m i n a t i o n r a t e . Th e e l i m i n a t i o nr a t e c o n s t a n t o f c l o x a c i l l i n was c a l c u l a t e d f r o m t h eA / V e x p o n e n t i a l l y d e c l i n i n g p a r t o f t h e s e ru m c o n c e n t r a -t i o n curve a f t e r t e r m i n a t i o n o f t h e c o n t i n u o u s i n f u -s i o n , o r f r o m t h e v a lu e s o b t a i n e d 1 h a f t e r a d m i n i s t r a -t i o n o f an i n t r a v e n o u s d o s e .A p p a r e n t v o l u m e o f d i s t r i b u t i o n . F o r t h e o n e-compartment m o d e l , t h e a p p a r e n t v o l u m e o f d i s t r i b u -t i o n ( V ) was c a l c u l a t e d b y d i v i d i n g t h e s i n g l e i n t r a v e -

I * c n o u s d o s e ( D ) b y t h e v a l u e o f t h e v i r t u a l c o n c e n t r a -t i o n a t t i m e zero ( C 0 ) . T h e l a t t e r v a l u e i s o b t a i n e d b y9 h o u r s e x t r a p o l a t i o n o f t h e e x p o n e n t i a l l y d e c l i n i n g p a r t o ft h e serum c o n c e n t r a t i o n curve t o t i m e z e r o :

V = DC o ( 1 )T h e a p p a r e n t v o l u m e o f d i s t r i b u t i o n o f c l o x a c i l l i nd u r i n g t h e c o n t i n u o u s i n f u s i o n ca n b e c a l c u l a t e d w i t ht h e f o l l o w i n g e q u a t i o n ( 1 0 ) :

A V = C t K . f o l C * d t ( 2 )i n w h i c h A , i s t h e amount a d m i n i s t e r e d up t o t i m e t ,V i s t h e a p p a r e n t v o l u m e o f d i s t r i b u t i o n , C , i s t h ec o n c e n t r a t i o n a t t i m e t , K i s t h e e l i m i n a t i o n r a t ec o n s t a n t , a n d f C C - d t i s t h e a r ea u n d e r t h e serumc o n c e n t r a t i o n curve f r o m t i m e zero t o t i m e t . A l i n e a rr e l a t i o n s h i p e x i s t s b e t w e e n A , a n d t h e r i g h t h a n d p a r to f t h e e q u a t i o n ; t h e s l o p e i s e q u a l t o V .

RESULTST a b l e 1 s h o w s t h e c a lc u l a t e d v a l u e s o f t h ea p p a r e n t v o l u m e o f d i s t r i b u t i o n ( V ) o f c l o x a c i l -l i n , g i v e n w i t h o u t or t o g e t h e r w i t h p r o b e n e c i d .

T A B L E 1 . A p p a r e n t v o l u m e o f d i s t r i b u t i o n a n d e x p o n e n t i a l e l i m i n a t i o n r a t e c o n s t a n t o f c l o x a c i l l i n w i t h o u t a n dw i t h p r o b e n e c i dV ( l i t e r ) K e i i m c ( h - 1 )

S u b j e c t a S e x - C l o x a - + C l o x - B o d y w t - A d m i n i s t r a t i o nClox l o x - k g ) - C l o x a - + C l o x -c i l l i n a c i l l i n c i l l i n a c i l l i nV M 1 5 . 7 1 5 . 8 5 8 0 . 2 7 8 0 . 2 3 6 I n f u s i o n dG M 1 3 . 1 1 3 . 5 5 8 0 . 3 9 0 0 . 3 2 2 I n f u s i o nB M 1 2 . 2 1 3 . 2 6 3 0 . 3 3 0 0 . 2 8 0 I n f u s i o nW F 1 0 . 1 9 . 8 6 4 0 . 3 5 8 0 . 3 1 9 O n e d o s e eG l F 8 . 8 1 0 . 8 5 0 0 . 2 7 5 0 . 1 5 6 One d o s eMean 0 . 3 2 6 0 . 2 6 3P F 1 5 . 4 1 4 . 6 6 9 0 . 5 4 3 0 . 3 6 3 C o u n t i n u o u s i n f u s i o nMean 1 2 . 6 1 3 . 0

a T h e f i r s t f i v e p a t i e n t s w e r e o n c h r o n i c i n t e r m i t t e n t h e m o d i a l y s i s ; t h e s i x t h h a d a c r e a t i n i n c l e a r a n c e o f 2 4m l / m i n . V , V o l u m e o f d i s t r i b u t i o n .c K e m , E x p o n e n t i a l e l i m i n a t i o n r a t e c o n s t a n t .d C o n t i n u o u s i n t r a v e n o u s i n f u s i o n .e S i n g l e i n t r a v e n o u s i n j e c t i o n .

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302 NAUTA, MATTIE, A N D GOSLINGST A B L E 2 . S e r u m c o n c e n t r a t i o n s o f c l o x a c i l l i n d u r i n g a n d a f t e r c o n t i n u o u s i n t r a v e n o u s i n f u s i o n w i t h o u t a n dw i t h ) r o b e n e c i d i n t h r e e p a t i e n t s o n c h r o n i c i n t e r m i t t e n t h e m o d i a l y s i s

S e r u m c o n c n ( p g / m l ) a f t e r a :S u b j e c t s P r o b e n e c i d l h 2h 3h 4h 5h 6h 7h 8h 9h

V _ 1 0 7 . 1 1 0 3 . 2 1 1 8 . 1 1 2 5 . 4 9 6 . 5 7 6 . 4 4 8 . 9 b 4 0 . 2 3 3 . 0 8 2 . 6 9 1 . 5 1 1 9 . 8 1 1 8 . 2 8 3 . 3 6 9 . 5 5 8 . 1 4 8 . 3 3 2 . 5G _ 8 5 . 4 9 9 . 6 1 0 4 . 0 . 1 0 6 . 3 6 5 . 2 3 5 . 0 2 6 . 3 1 9 . 6 1 5 . 1 c 1 0 6 . 4 1 2 7 . 9 1 2 1 . 4 7 2 . 9 1 5 2 . 2 3 9 . 5 2 7 . 5 2 4 . 4B - 8 8 . 9 1 0 7 . 2 1 1 7 . 7 1 2 7 . 0 8 7 . 0 6 1 . 1 4 5 . 3 3 3 . 7 2 3 . 7 9 4 . 5 1 1 0 . 1 1 3 0 . 8 1 2 8 . 7 1 0 4 . 7 6 8 . 5 5 3 . 1 4 0 . 8 3 3 . 0

a I n f u s i o n l a s t e d f o r f i r s t 4 h .T i m e , 7 . 1 7 h .T i m e , 8 . 8 3 h .F o r e a c h i n d i v i d u a l p a t i e n t , t h e a p p a r e n t v o l -ume o f d i s t r i b u t i o n was a l m o s t t h e same u n d e rb o t h c i r c u m s t a n c e s . Th e mean v a l u e s u n d e r t h et w o c o n d i t i o n s ( 1 2 . 6 a n d 1 3 . 0 l i t e r s , r e s p e c -t i v e l y ) d i d n o t d i f f e r s i g n i f i c a n t l y ( 0 . 3 0 < P


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PROBENECID EFFECT ON CLOXACILLIN ELIMINATION 303serum c o n c e n t r a t i o n s , t h e r e i s no rea s o n t oassume t h a t t h e c o nc e n t r a t i o n i n t h e t i s s u e s i sn o t a l s o h i g h e r i n p r o b e n e c i d - t r e a t e d p a t i e n t s .T h e r e f o r e , t h e r e i s no r e a s o n t o s u p p o s e t h a tu n d e r t h e i n f l u e n c e o f p r o b e n e c i d a l o w e r c o n -c e n t r a t i o n o f a p e n i c i l l i n w i l l e x i s t a t t h e s i t e o fan i n f e c t i o n .I n o ur o p i n i o n , p r o b e n e c i d ca n b e u s e d s a f e l ya n d w i t h p r o f i t i n p a t i e n t s wh o n e e d h i g hc o n c e n t r a t i o n s o f a p e n i c i l l i n .I t i s a l s o i n t e r e s t i n g t h a t , i n s p i t e o f t h ec o m p l e t e a b s e n c e o f k i d n e y f u n c t i o n , a n u r i cp a t i e n t s s h o w a s i g n i f i c a n t r e d u c t i o n o f t h ee l i m i n a t i o n . I t i s e v i d e n t t h a t p r o b e n e c i d d i -m i n i s h e s n o t o n l y t h e r e n a l b u t a l s o t h e e x t r a r e -n a l e l i m i n a t i o n . T h i s p h e n o m e n o n ca n p o s s i b l yb e e x p l a i n e d b y a b l o c k a d e o f t h e e l i m i n a t i o nb y t h e l i v e r . T h i s p o s s i b i l i t y i s s u p p o r t e d b yF i s h m a n ' s ( 3 ) o b s e r v a t i o n t h a t p r o b e n e c i d r e -d u c e s t h e r a t i o o f t h e l i v e r - t o - s e r u m c o n c e n t r a -t i o n o f b e n z y l p e n i c i l l i n i n n e p h r e c t o m i z e d d o g s .T h e u p t a k e o f o t h e r d r u g s b y t h e l i v e r , i n c l u d -i n g r i f a m y c i n ( 7 ) , i s a l s o d e c r e a s e d , l e a d i n g t o as l o w e r e l i m i n a t i o n .

ACKNOWLEDGMENTSWe w i s h t o t h a n k W i n y L o s f o r h e r e x c e l l e n t t e c h n i c a la s s i s t a n c e a n d R a l p h va n F u r t h f o r h i s v a l u a b l e h e l p i n t h ep r e p a r a t i o n o f t h i s paper.

LITERATURE CITED1 . B r a z e a u , P . 1 9 7 0 . I n L . S . Goodman a n d A . G i l m a n ( e d . ) ,T h e p h a r m a c o l o g i c a l b a s i s o f t h e r a p e u t i c s , 4 t h e d . ,

p . 8 8 8 - 8 8 9 . T h e M a c m i l l a n C o . , Ne w Y o r k .2 . D a y t o n , P . G . , T . F . Y i i , W . C h e n , L . B e r g e r , L . A . W e s t ,a n d A . B . G u t m a n . 1 9 6 3 . T h e p h y s i o l o g i c a l d i s p o s i t i o no f p r o b e n e c i d , i n c l u d i n g r e n a l c l e a r a n c e , i n m a n ,s t u d i e d b y a n i m p r o v e d m e t h o d f o r i t s e s t i m a t i o n i nb i o l o g i c a l m a t e r i a l . J . P h a r m a c o l . E x p . T h e r .1 4 0 : 2 7 8 - 2 8 6 .3 . F i s h m a n , R . A . 1 9 6 6 . B l o o d - b r a i n a n d CSF b a r r i e r s t op e n i c i l l i n a n d r e l a t e d o r g a n i c a c i d s . A r c h . N e u r o l .1 5 : 1 1 3 - 1 2 4 .4 . G i b a l d i , M . , D . D a v i d s o n , M. E . P l a u t , a n d M. A .S c h w a r t z . 1 9 7 0 . M o d i f i c a t i o n o f p e n i c i l l i n d i s t r i b u t i o na n d e l i m i n a t i o n b y p r o b e n e c i d . I n t . J . C l i n . P h a r m a -c o l . 3 : 1 8 2 - 1 8 9 .5 . G i b a l d i , M . , a n d M. A . S c h w a r t z . 1 9 6 8 . A p p a r e n t e f f e c to f p r o b e n e c i d o n t h e d i s t r i b u t i o n o f p e n i c i l l i n s i n m a n .C l i n . P h a r m a c o l . T h e r . 9 : 3 4 5 - 3 4 9 .6 . G r o v e , D . C . , a n d W. A . R a n d a l l . 1 9 5 5 . A s s a y m e t h o d s o fa n t i b i o t i c s . A l a b o r a t o r y m a n u a l . M e d i c a l E n c y -c l o p e d i a , Ne w Y o r k .7 . K e n w r i g h t , S . , a n d A . J . L e v i . 1 9 7 3 . I m p a i r m e n t o fh e p a t i c u p t a k e o f r i f a m y c i n a n t i b i o t i c s b y p r o b e n e c i d ,a n d i t s t h e r a p e u t i c i m p l i c a t i o n s . L a n c e t I I : 1 4 0 1 - 1 4 0 5 .8 . M a t t i e , H . , W. R . 0 . G o s l i n g s , a n d E . L . N o a c h . 1 9 7 3 .C l o x a c i l l i n a n d n a f c i l l i n : s e r u m b i n d i n g a n d i t s r e l a -t i o n s h i p t o a n t i b a c t e r i a l e f f e c t i n m i c e . J . I n f e c t . D i s .1 2 8 : 1 7 0 - 1 7 7 .9 . N a u t a , E . H . , H . M a t t i e , a n d W. R . 0 . G o s l i n g s . 1 9 7 3 .P h a r m a c o k i n e t i c s o f c l o x a c i l l i n i n p a t i e n t s o n c h r o n i ci n t e r m i t t e n t h a e m o d i a l y s i s a n d i n h e a l t h y s u b j e c t s .C h e m o t h e r a p y 1 9 : 2 6 1 - 2 7 1 .1 0 . W a g n e r , J . G . , a n d E . N e l s o n . 1 9 6 4 . K i n e t i c a n a l y s i s o fb l o o d l e v e l s a n d u r i n a r y e x c r e t i o n i n t h e a b s o r p t i v ep h a s e a f t e r s i n g l e d o s e s o f d r u g . J . P h a r m . S c i .5 3 : 1 3 9 2 - 1 4 0 3 .1 1 . W e i n e r , I . M . , J . A . W a s h i n g t o n , a n d G . H . M u d g e . 1 9 6 0 .On t h e m e c h a n i s m o f a c t i o n o f p r o b e n e c i d o n r e n a lt u b u l a r s e c r e t i o n . B u l l . J o h n s H o p k i n s H o s p .1 0 6 : 3 3 6 - 3 4 6 .

V O L . 6 , 1 9 7 4


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