P H A R M A C O K I N E T I C S OF S A L I C Y L A T E AFTER CHRONIC D O S I N G I N MAN L . J . Aarons, F. Bochner, D.M. Johns and M. Rowland, Department of Pharmacy, U n i v e r s i t y of Manchester, Manchester, M13 9PL, U.K.; Department o f Medicine, Royal B r i s b a n e H o s p i t a l , Brisbane 4029, Australia S a l i c y l a t e dosage i s e m p i r i c a l ; o f t e n i t i n v o l v e s i n c r e a s i n g t h e dose u n t i l s i d e e f f e c t s develop and t h e n d e c r e a s i n g t h e dosage s l i g h t l y . P r e d i c t i o n of i n d i v i d u a l s a l i c y l a t e dosage i s hampered by i t s w e l l r e c o g n i s e d dose dependent k i n e t i c s (Levy, 1965). Most d e t a i l e d k i n e t i c s t u d i e s have been based on s i n g l e dose u r i n e d a t a . The p r e s e n t s t u d y emphasises c h r o n i c a d m i n i s t r a t i o n and unbound drug i n plasma. Two h e a l t h y male v o l u n t e e r s who gave t h e i r informed c o n s e n t , e a c h i n g e s t e d 300 mg a s p i r i n , i n s o l u t i o n , e v e r y e i g h t h o u r s u n t i l s t e a d y s t a t e was r e a c h e d . Blood, u r i n e and s a l i v a was t h e n c o l l e c t e d . The procedure was r e p e a t e d , r a i s i n g t h e dose by increments of 300 mg, u n t i l s i d e e f f e c t s , g a s t r o - i n t e s t i n a l d i s c o m f o r t and t i n n i t u s , o c c u r r e d . A t t h a t t i m e , one s u b j e c t was t a k i n g 1200 mg and t h e o t h e r 1500 mg e v e r y e i g h t h o u r s . On a s e p a r a t e o c c a s i o n , e a c h s u b j e c t i n g e s t e d 2 . 4 g aspirin i n solution. S a l i c y l i c a c i d i n plasma w a s measured by f l u o r i m e t r y . Salicylic acid, salicylu r i c a c i d and g e n t i s i c w a s measured by h p l c . T o t a l u r i n a r y s a l i c y l a t e was d e t e r m i n e d c o l o u r i m e t r i c a l l y (Levy and P r o c k n a l , 1968). Plasma b i n d i n g was measured by u l t r a c e n t r i f u g a t i o n . The mean s t e a d y s t a t e plasma and unbound c o n c e n t r a t i o n i n c r e a s e d d i s p r o p o r t i o n a l l y w i t h dose. S a l i c y l u r i c a c i d was t h e major u r i n a r y m e t a b o l i t e ; b u t due t o s a t u r a t i o n o f t h i s pathway t h e p e r c e n t e x c r e t e d d e c r e a s e d from 80% t o 60% upon i n c r e a s i n g from t h e lowest t o h i g h e s t dose. The b i n d i n g o f s a l i c y l a t e a l s o d e c r e a s e d w i t h i n c r e a s i n g plasma c o n c e n t r a t i o n . A l l t h e d a t a - unbound s a l i c y l a t e i n plasma and t h e cumulative s a l i c y l u r a t e exc r e t e d i n u r i n e a t s t e a d y s t a t e a t each dose l e v e l - were f i t t e d s i m u l t a n e o u s l y u s i n g a n o n l i n e a r r e g r e s s i o n programme, t o a p h a r m a c o k i n e t i c model which i s based on unbound drug i n plasma and two pathways o f e l i m i n a t i o n , one s a t u r a b l e ( s a l i c y l u r a t e f o r m a t i o n ) and one n o n - s a t u r a b l e ( o t h e r pathways). Attempts t o f i t t h e plasma d a t a a l o n e f a i l e d . S i m u l a t i o n from t h e f i t s of t h e s i n g l e dose d a t a overp r e d i c t e d t h e s t e a d y s t a t e s a l i c y l a t e plasma c o n c e n t r a t i o n d a t a . L i k e l y explanat i o n s i n c l u d e , d e c r e a s e s i n plasma b i n d i n g and s t i m u l a t i o n o f s a l i c y l u r a t e m e t abo 1i s m . T i n n i t u s w a s n o t e d a t plasma s a l i c y l a t e c o n c e n t r a t i o n above 100 mg/L. Both subj e c t s e x p e r i e n c e d some h e a r i n g l o s s a t t h e h i g h e s t d o s i n g r a t e ; h e a r i n g recovered upon withdrawing a s p i r i n . Levy, G.

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