A Novel Method for the Detection of Drug Induced Gastrointestinal Irritancy

Abstract

I t i s e s t a b l i s h e d t h a t most, if n o t a l l , n o n -s t e r o i d a l a n t i -i n f l a m m a t o r y d r u g s (NSAID) induce g a s t r o i n t e s t i n a l damage (Menguy 1 9 7 2 ) . The development of a s i m p l e i n v i t r o method f o r q u a n t i f y i n g t h i s mucosal e p i t h e l i a l damage i s d e s c r i b e d . The t e r m i n a l ileum was removed from m a l e Wistar r a t s (180-250 9 . ) and p e r f u s e d through i t s lumen a t 3 m l /min f o r 3 h o u r s w i t h Krebs s o l u t i o n a t 37OC. bubbled w i t h 5 % co e f f l u e n t from t h e ileum and weighing t h e r e s i d u a l m U C O S a l C e l l s . t e s t was added t o the r e s e r v o i r p r i o r t o p e r f u s i o n Of the i k u m and the r e s u l t was compared w i t h an a d j a c e n t s e c t i o n o f t i s s u e p e r f u s e d w i t h Krebs s o l u t i o n a l o n e . t i s s u e .The mucosal damage induced by indomethacin, a known i n t e s t i n a l i r r i t a n t (Fang e t a1 1 9 7 6 ) , w a s feud t o be dose dependent. ( F i a . 1 ) . Fig. 1 : Mucosal e p i t h e l i a l loss and 02' MucOSal damage w a s determined by f i l t e r i n g t h e 2 The drug under A l l r e s u l t s are e x p r e s s e d a s a p e r c e n t a g e of t h e w e t w e i g h t of t h e I II 111 due t o indomethacin, i. Indomethacin 7pM (n=9) ii. Indomethacin 14pM (n=9) iii, Indomethacin 28pM (n=6) Ir A s p i r i n (330pM) and phenylbutazone (129uM) also caused a s i g n r f i c a n t mucosal loss o f 3.8 _+ 0.7% (n = 5, p < 0.01) and 6.2 _+ 1.1% (n = 11, p < 0.001) r e s p e c t i v e l y . However, n e i t h e r p a r a c e t a m o l (660uM), a drug w i t h minimal g a s t r o i n t e s t i n a l i r r i t a n c y , nor d i c l o f e n a c ( 2 1 0 u M ) , a new NSAID, caused any s i g n i f i c a n t mucosal l o s s . p r e s e n c e of indomethacin (28uM), p r e v e n t e d t h e mucosal loss produced by indomethacin a l o n e . An e x p l a n a t i o n f o r t h e r e s u l t s i s t h a t i n h i b i t i o n o f p r o s t a g l a n d i n s y n t h e s i s i n t h e g a s t r o i n t e s t i n a l t r a c t may be t h e mechanism i n v o l v e d i n mucosal loss, w h i l s t t h e p r e v e n t i o n of mucosal l o s s by PGE i s c o n s i s t e n t w i t h t h e known c y t op r o t e c t i v e a c t i o n of p r o s t a g l a n d i n s ( h o b e r t The c o r r e l a t i o n between the r e s u l t s o f t h i s s t u d y and t h e known i n t e s t i n a l i r r i t a n c y of t h e d r u g s s t u d i e d ( R a i n s f o r d 1975; Yanagi e t a 1 1978) i n d i c a t e s t h e v a l i d i t y o f t h e method as a simple s c r e e n f o r g a s t r o i n t e s t i n a l i r r i t a n t s . ROW. i s an S.R.C. s t u d e n t . W e thank D r . J. Pike (Upjohn C o . ) f o r p r o s t a g l a n d i n s and Geigy f o r d i c l o f e n a c ( " V o l t a r o l " ) .R a i n s f o r d , K.D. (1975) Agents A c t i o n s 5: 326-344 Robert, A. (1975) G a s t r o e n t e r o l o g y 69: 1045-1047 Yanagi, Y. e t a1 (1978) ...