55p
S T ~ ~ I EON S THE HYPOGLYCAEMIC ACTION OF GLICLAZIDE, A SULPHONYL-
@A
DRUG
B , ~ . ~ u r m a nand M.O. tlusbah, Department of Physiology and Pharmacology, o f S t r a t h c l y d e , George S t r e e t , Glasgow G1 1XW. Sulphonylurea d r u g s are e f f e c t i v e i n l o w e r i n g blood g l u c o s e i n m a t u r i t y o n s e t diabetic patients. G l i c l a z i d e i s a r e l a t i v e l y new s u l p h o n y l u r e a compound which, u n l i k e p r e v i o u s d r u g s , a p p e a r s t o have a p r o t e c t i v e e f f e c t on t h e microc i r c u l a t i o n i n d i a b e t e s (Duhault & o t h e r s , 1 9 7 2 ) . Although i n s u l i n s e c r e t i o n h a s been shown u n i v e r s a l l y t o be s t i m u l a t e d by s u l p h o n y l u r e a d r u g s , evidence h a s been p r e s e n t e d t o i m p l i c a t e e x t r a - p a n c r e a t i c mechanism i n t h e hypoglycaemic The aim o f t h e w o r k a c t i o n o f t h e s e compounds (Feldman & o t h e r s , l 9 7 1 ) . p r e s e n t e d i n t h i s r e p o r t w a s t o i n v e s t i g a t e t h e r o l e o f i n s u l i n i n t h e hypoglycaemic a c t i o n o f q l i c l a z i . d e and t o examine t h e p o s s i b i l i t y t h a t p a r t o f t h e a c t i o n of t h e drug may i n v o l v e augmentation of t h e e f f e c t s o f i n s u l i n . Some comparisons a r e made w i t h g l i b e n c l a m i d e . Male Wistar r a t s w e r e used throughout. In some experiments t h e d r u g o r c o n t r o l s o l u t i o n s were i n j e c t e d i . p . and blood removed a t t h e d e s i r e d t i m e from t h e f e m o r a l v e i n u s i n g l i g h t e t h e r a n a e s t h e s i a . I n most experiments animals were p r e p a r e d 48h b e f o r e u s e by p l a c i n g f i n e polyaerie cannulae i n t h e abdominal a o r t a ( f o r blood sampling) and t h e r i g h t e x t e r n a l The cannulae were e x t e r i o r i z e d on t h e d o r s a l j ugul ar vein ( f o r i . v . i n j e c t i o n ) . s u r f a c e of t h e neck. I n t h e s e a n i m a l s s o l u t i o n s c o u l d b e i n j e c t e d and s e r i a l blood samples o b t a i n e d w i t h o u t a n a e s t h e s i a and w i t h t h e minimum of h a n d l i n g of t h e r a t s . Plasma was a n a l y s e d f o r g l u c o s e , f r e e f a t t y a c i d s (FFA)and immunoreactive insulin ( I R I )
.
I n f a s t e d r a t s g l i c l a z i d e ( 1 - 2 0 mg/kg) o r g l i b e n c l a m i d e (0.05-1 mg/kg) produced dose-dependent d e c r e a s e s i n plasma g l u c o s e and plasma FFA c o n c e n t r a t i o n s . The hypoglycaemic a c t i o n w a s a p p a r e n t a t 5 minutes a f t e r i n j e c t i o n and t h e d u r a t i o n o f t h e e f f e c t was d o s e r e l a t e d . Both d r u q s produced d o s e dependent i n c r e a s e s Sub-maximal hypoglycaemic d o s e s of g l i b e n i n t h e plasma I R I c o n c e n t r a t i o n . clamide produced g r e a t e r i n c r e a s e s i n plasma I R I c o n c e n t r a t i o n s t h a n t h o s e produced by g l i c l a z i d e d e s p i t e s i m i l a r glycaemic r e s p o n s e s . Plasma I R I concent r a t i o n s were t r a n s i e n t l y i n c r e a s e d by g l i c l a z i d e , showing e l e v a t i o n above t h e c o n t r a 1 l e v e l a t 5 minutes b u t n o t a t 30 minutes a f t e r i n j e c t i o n . Injected i n s u l i n was found t o d i s a p p e a r r a p i d l y from r a t plasma i n v i v o . N e i t h e r g l i c l a z i d e (1-10 mg/kg) n o r g l i b e n c l a m i d e (0.05 mg/kq) produced any augmentation o f t h e e f f e c t s o f i n s u l i n (0.1-1 U/kg) i n l o w e r i n g plasma g l u c o s e o r FFA c o n c e n t r a t i o n s . I n a l l o x a n d i a b e t i c r a t s ( a l l o x a n 65 mg/kg i.v.65hours b e f o r e t h e experiment) n e i t h e r g l i c l a z i d e n o r g l i b e n c l a m i d e produced any r e d u c t i o n i n g l u c o s e or FFA c o n c e n t r a t i o n s and f a i l e d t o e l e v a t e t h e plasma I R I c o n c e n t r a t i o n s . Moreo v e r t h e plasma g l u c o s e and FFA-lowering a c t i o n s o f i n s u l i n (O.S-lU/kg) were n o t augmented by g l i c l a z i d e i n t h e s e animals. The r e s u l t s s u g g e s t t h a t t h e a c u t e hypoglycaemic a c t i o n o f g l i c l a z i d e i s mediated by t h e observed i n c r e a s e s i n plasma I R I c o n c e n t r a t i o n s and t h a t t h e two drugs examined do n o t have any i m p o r t a n t a c t i o n i n augmenting t h e e f f e c t s of i n s u l i n . I t i s d i f f i c u l t t o d e m o n s t r a t e t h e importance o f e x t r a p a n c r e a t i c e f f e c t s i n t h e i n t a c t r a t , i n which i n s u l i n s e c r e t i o n i s i n v a r i a b l y i n c r e a s e d by s u l p h o n y l u r e a s . The a c u t e l y d i a b e t i c r a t shows a d e g r e e o f i n s u l i n i n s e n s i t i v i t y and t h u s may n o t b e t h e b e s t model i n which t o s t u d y e x t r a p a n c r e a t i c a c t i o n s . Moreover e x t r a p a n c r e a t i c a c t i o n s may a p p e a r o n l y d u r i n g prolonged t r e a t m e n t w i t h t h e s e d r u g s .
W e gratefully acknowledge S e r v i e r L a b o r a t o r i e s f o r f i n a n c i a l s u p p o r t and g i f t s Of g l i c l a z i d e . Glibenclamide w a s a g i f t from Hoechst P h a r m a c e u t i c a l s . Duhault, J . and Lebon, F. (1972). Arzneim-Forsch., 2 2 , 1686-1690. Feldman, J . M . and L e b o v i t z , H.E. (1971). D i a b e t e s , 2 0 , 745-755.
S T ~ ~ I EON S THE HYPOGLYCAEMIC ACTION OF GLICLAZIDE, A SULPHONYL-
@A
DRUG
B , ~ . ~ u r m a nand M.O. tlusbah, Department of Physiology and Pharmacology, o f S t r a t h c l y d e , George S t r e e t , Glasgow G1 1XW. Sulphonylurea d r u g s are e f f e c t i v e i n l o w e r i n g blood g l u c o s e i n m a t u r i t y o n s e t diabetic patients. G l i c l a z i d e i s a r e l a t i v e l y new s u l p h o n y l u r e a compound which, u n l i k e p r e v i o u s d r u g s , a p p e a r s t o have a p r o t e c t i v e e f f e c t on t h e microc i r c u l a t i o n i n d i a b e t e s (Duhault & o t h e r s , 1 9 7 2 ) . Although i n s u l i n s e c r e t i o n h a s been shown u n i v e r s a l l y t o be s t i m u l a t e d by s u l p h o n y l u r e a d r u g s , evidence h a s been p r e s e n t e d t o i m p l i c a t e e x t r a - p a n c r e a t i c mechanism i n t h e hypoglycaemic The aim o f t h e w o r k a c t i o n o f t h e s e compounds (Feldman & o t h e r s , l 9 7 1 ) . p r e s e n t e d i n t h i s r e p o r t w a s t o i n v e s t i g a t e t h e r o l e o f i n s u l i n i n t h e hypoglycaemic a c t i o n o f q l i c l a z i . d e and t o examine t h e p o s s i b i l i t y t h a t p a r t o f t h e a c t i o n of t h e drug may i n v o l v e augmentation of t h e e f f e c t s o f i n s u l i n . Some comparisons a r e made w i t h g l i b e n c l a m i d e . Male Wistar r a t s w e r e used throughout. In some experiments t h e d r u g o r c o n t r o l s o l u t i o n s were i n j e c t e d i . p . and blood removed a t t h e d e s i r e d t i m e from t h e f e m o r a l v e i n u s i n g l i g h t e t h e r a n a e s t h e s i a . I n most experiments animals were p r e p a r e d 48h b e f o r e u s e by p l a c i n g f i n e polyaerie cannulae i n t h e abdominal a o r t a ( f o r blood sampling) and t h e r i g h t e x t e r n a l The cannulae were e x t e r i o r i z e d on t h e d o r s a l j ugul ar vein ( f o r i . v . i n j e c t i o n ) . s u r f a c e of t h e neck. I n t h e s e a n i m a l s s o l u t i o n s c o u l d b e i n j e c t e d and s e r i a l blood samples o b t a i n e d w i t h o u t a n a e s t h e s i a and w i t h t h e minimum of h a n d l i n g of t h e r a t s . Plasma was a n a l y s e d f o r g l u c o s e , f r e e f a t t y a c i d s (FFA)and immunoreactive insulin ( I R I )
.
I n f a s t e d r a t s g l i c l a z i d e ( 1 - 2 0 mg/kg) o r g l i b e n c l a m i d e (0.05-1 mg/kg) produced dose-dependent d e c r e a s e s i n plasma g l u c o s e and plasma FFA c o n c e n t r a t i o n s . The hypoglycaemic a c t i o n w a s a p p a r e n t a t 5 minutes a f t e r i n j e c t i o n and t h e d u r a t i o n o f t h e e f f e c t was d o s e r e l a t e d . Both d r u q s produced d o s e dependent i n c r e a s e s Sub-maximal hypoglycaemic d o s e s of g l i b e n i n t h e plasma I R I c o n c e n t r a t i o n . clamide produced g r e a t e r i n c r e a s e s i n plasma I R I c o n c e n t r a t i o n s t h a n t h o s e produced by g l i c l a z i d e d e s p i t e s i m i l a r glycaemic r e s p o n s e s . Plasma I R I concent r a t i o n s were t r a n s i e n t l y i n c r e a s e d by g l i c l a z i d e , showing e l e v a t i o n above t h e c o n t r a 1 l e v e l a t 5 minutes b u t n o t a t 30 minutes a f t e r i n j e c t i o n . Injected i n s u l i n was found t o d i s a p p e a r r a p i d l y from r a t plasma i n v i v o . N e i t h e r g l i c l a z i d e (1-10 mg/kg) n o r g l i b e n c l a m i d e (0.05 mg/kq) produced any augmentation o f t h e e f f e c t s o f i n s u l i n (0.1-1 U/kg) i n l o w e r i n g plasma g l u c o s e o r FFA c o n c e n t r a t i o n s . I n a l l o x a n d i a b e t i c r a t s ( a l l o x a n 65 mg/kg i.v.65hours b e f o r e t h e experiment) n e i t h e r g l i c l a z i d e n o r g l i b e n c l a m i d e produced any r e d u c t i o n i n g l u c o s e or FFA c o n c e n t r a t i o n s and f a i l e d t o e l e v a t e t h e plasma I R I c o n c e n t r a t i o n s . Moreo v e r t h e plasma g l u c o s e and FFA-lowering a c t i o n s o f i n s u l i n (O.S-lU/kg) were n o t augmented by g l i c l a z i d e i n t h e s e animals. The r e s u l t s s u g g e s t t h a t t h e a c u t e hypoglycaemic a c t i o n o f g l i c l a z i d e i s mediated by t h e observed i n c r e a s e s i n plasma I R I c o n c e n t r a t i o n s and t h a t t h e two drugs examined do n o t have any i m p o r t a n t a c t i o n i n augmenting t h e e f f e c t s of i n s u l i n . I t i s d i f f i c u l t t o d e m o n s t r a t e t h e importance o f e x t r a p a n c r e a t i c e f f e c t s i n t h e i n t a c t r a t , i n which i n s u l i n s e c r e t i o n i s i n v a r i a b l y i n c r e a s e d by s u l p h o n y l u r e a s . The a c u t e l y d i a b e t i c r a t shows a d e g r e e o f i n s u l i n i n s e n s i t i v i t y and t h u s may n o t b e t h e b e s t model i n which t o s t u d y e x t r a p a n c r e a t i c a c t i o n s . Moreover e x t r a p a n c r e a t i c a c t i o n s may a p p e a r o n l y d u r i n g prolonged t r e a t m e n t w i t h t h e s e d r u g s .
W e gratefully acknowledge S e r v i e r L a b o r a t o r i e s f o r f i n a n c i a l s u p p o r t and g i f t s Of g l i c l a z i d e . Glibenclamide w a s a g i f t from Hoechst P h a r m a c e u t i c a l s . Duhault, J . and Lebon, F. (1972). Arzneim-Forsch., 2 2 , 1686-1690. Feldman, J . M . and L e b o v i t z , H.E. (1971). D i a b e t e s , 2 0 , 745-755.
