PLASMA CONCENTRATION-TIME PROFILE OF A SINGLE DOSE
OF ENTERIC-COATED OMEPRAZOLE IN M
ALE AND FEM
ALE
HEALTHY VOLUNTEERS
Ece İs k e n d e r, M.Sc. / N eslihan A slan, M .D ., Ph.D.
M . Z a fe r G ö re n , M .D ., Ph.D. / Tahir T e llio ğ lu , M .D . / Serap A k ın , M .D .
N u ra y Erin, M .D . / Rezzan A k e r, M .D . / Filiz O n at, M .D ., Ph.D.
K em al B erkm an , M .D . / Şule O k ta y , M .D ., Ph.D.
* D e p a rtm e n t o f P h a rm a c o lo g y a n d C lin ic a l P h a rm a co lo g y, S c h o o l o f M edicine, M a rm a ra U n ive rsity, is ta n b u l, Turkey.
ABSTRACT
O b je c t iv e : T h e b io a v a ila b ility o f a s in g le d o s e (2 0 m g ) o f tw o e n te r ic - c o a te d o m e p r a z o le fo rm u la tio n s , m a rk e te d in T u rk e y , g iv e n 1 0 -1 5 m in b e fo re b re a k fa s t, w a s s tu d ie d in 12 h e a lth y v o lu n te e rs (6 m a le s a n d 6 fe m a le s ) in a d o u b le b lin d , c ro s s o v e r d e s ig n . M e t h o d s : B lo o d s a m p le s w e re c o lle c te d p rio r to a n d a t 10 tim e p o in ts w ith in 12 h rs. a fte r d o s in g . P la s m a o m e p r a z o le c o n c e n tr a tio n s w e re m e a s u re d b y H P L C te c h n iq u e in o u r la b o ra to ry .R e s u lt s a n d C o n c lu s io n s : T h e tw o p ro d u c ts w e re fo u n d to b e b io e q u iv a le n t in te rm s o f e x te n t o f a b s o r p tio n (th e a re a u n d e r th e p la s m a c o n c e n tr a tio n -tim e c u rv e s ). M u ltip e a k p la s m a c o n c e n tra tio n p ro file s w e re s e e n in m o s t of th e s u b je c ts w ith b o th p ro d u c ts . T im e to th e e a rlie r p e a k s w a s 1 -2 h rs . a n d th o s e p e a k s w e re lo w e r in a m p litu d e th a n th e p e a k s re a c h e d a p p r o x im a te ly 4 .5 h rs . a fte r th e a p p lic a tio n . In te re s tin g ly , th e m u ltip e a k p ro file w a s m o re fre q u e n t a n d th e e a rlie r p e a k s w e re s ig n ific a n tly h ig h e r in fe m a le s u b je c ts th a n in m a le s . T h e re a s o n fo r th is g e n d e r d iffe re n c e in m u ltip e a k p la s m a c o n c e n tr a tio n - tim e p r o file o f o ra l o m e p ra z o le n e e d s fu r th e r in v e s tig a tio n .
K ey W ords:
O m e p ra z o le - B io a v a ila b ility - E n te ric - c o a te d c a p s u le s - G e n d e r d iffe re n c eINTRODUCTION
O m e p r a z o le , a s u b s titu te d b e n z im id a z o le d e riv a tiv e c a u s e s th e p o te n t a n d lo n g -la s tin g in h ib itio n o f g a s tric a c id s e c re tio n b y s e le c tiv e ly in te ra c tin g w ith th e g a s tric p ro to n p u m p (h+-k+- A T P a s e ) in th e p a rie ta l c e ll s e c re to ry m e m b ra n e (1 -3 ). T h e d e g re e o f g a s tric a c id s u p p re s s io n is c o r r e la te d w ith th e a re a u n d e r th e p la s m a o m e p ra z o le c o n c e n tr a tio n -tim e c u rv e (A U C ) a n d n o t d ire c tly re la te d to th e p la s m a c o n c e n tra tio n of th e d ru g a t a n y g iv e n tim e (4). T h e lo n g la s tin g e ffe c t o f o m e p ra z o le o n th e H+-K + -A T P a se in th e p a rie ta l c e lls , d e s p ite its s h o rt p la s m a h a lf life, a c c o u n ts fo r th e la c k o f c o rre la tio n b e tw e e n p la s m a c o n c e n tr a tio n a n d d e g re e o f a c id in h ib itio n (2). S in c e o m e p r a z o le is a c id la b ile , a c id -re s is ta n t e n te ric -c o a te d g ra n u le s o r c a p s u le s h a v e b e e n d e v e lo p e d . A lth o u g h th e e x te n t of a b s o rp tio n w a s r e p o r te d n o t to b e in flu e n c e d b y th e p re s e n c e o f fo o d in th e s to m a c h , m u ltip e a k o r s in g le -p e a k p la s m a c o n c e n tra tio n -tim e p ro file s w e re fo u n d a fte r th e o ra l a d m in is tra tio n of o m e p r a z o le a d m in is te r e d b e fo r e a n d a fte r
Ece İskender, et al
b re a k fa s t, re s p e c tiv e ly . T h e p re s e n t s tu d y w a s p la n n e d to in v e s tig a te th e b io a v a ila b ility a n d p la s m a c o n c e n tr a tio n -tim e p ro file s a fte r a s in g le o ra l d o s e o f tw o o m e p r a z o le fo r m u la tio n s m a rk e te d in T u rk e y in m a le a n d fe m a le h e a lth y v o lu n te e rs . B o th p re p a ra tio n s a re in d e la y e d re le a s e , e n te ric -c o a te d , c a p s u le fo rm s .
MATERIAL A ND METHOD
S u b je c t s : T w e lv e h e a lth y a d u lt v o lu n te e rs (6 fe m a le s , 6 m a le s ) a g e d b e tw e e n 2 0 -2 6 y e a rs , w e ig h in g 4 9 -8 7 kg w e re in c lu d e d in th e s tu d y . T h e s u b je c ts w e r e a s s e s s e d b y a m e d ic a l h is to ry , p h y s ic a l e x a m in a tio n , b io c h e m ic a l in v e s tig a tio n s fo r k id n e y a n d liv e r fu n c tio n s a n d h e m a to lo g ic a l e x a m in a tio n s ; th e v a lu e s a n d fin d in g s w e re w ith in th e n o rm a l lim its . N o n e o f th e s u b je c ts re c e iv e d a n y o th e r m e d ic a tio n fo r 4 w e e k s p rio r to th e s tu d y a n d d u rin g th e s tu d y p e rio d . T h e s tu d y w a s c o n d u c te d in a c c o rd a n c e w ith th e D e c la ra tio n o f H e ls in k i. A fu lly in fo rm e d w ritte n c o n s e n t w a s o b ta in e d fr o m e a c h v o lu n te e r. T h e s tu d y w a s a p p ro v e d b y th e E th ic s C o m m itte e o f M a rm a ra U n iv e rs ity , S c h o o l o f M e d ic in e . S t u d y d e s ig n : A ra n d o m iz e d , d o u b le b lin d , c ro s s o v e r d e s ig n w ith a w a s h o u t p e rio d o f 7 d a y s b e tw e e n th e tre a tm e n ts w a s u s e d . E a c h s u b je c t re c e iv e d o n e c a p s u le o f e ith e r p ro d u c t "A " o r "B " (2 0 m g o m e p ra z o le ) a t 8 :0 0 -9 :0 0 a .m . o n e w e e k a p a rt. A s ta n d a rd b re a k fa s t w a s g iv e n 1 0 -1 5 m in u te s a fte r th e d ru g a d m in is tra tio n to all th e v o lu n te e rs . C a lo rie in ta k e a n d p h y s ic a l e x e rc is e w e re a ls o s ta n d a rd iz e d d u rin g th e s tu d y p e rio d . B lo o d s a m p le s (5 m l e a c h ) w e re c o lle c te d b y v e n ip u n c tu r e fr o m th e fo r e a r m a t 0 ,1 ,2 ,2 .5 ,3 ,3 .5 ,4 ,5 ,6 ,8 a n d 12 h rs. a fte r th e d ru g a d m in is tr a tio n .T h e p la s m a w a s s e p a r a te d im m e d ia te ly b y c e n trifu g a tio n a t 3 0 0 0 rp m fo r 10 m in u te s a n d w a s b u ffe re d b y a d d in g 4 pi o f 1.0 M s o d iu m c a rb o n a te p e r m l o f p la s m a . T h e s a m p le s w e re s to r e d a t - 7 0 ° C u n til a s s a y e d fo r o m e p ra z o le . A n a ly s is : P la s m a o m e p ra z o le c o n c e n tra tio n s w e re m e a s u r e d b y h ig h p e r fo r m a n c e liq u id c h ro m a to g ra p h y (H P L C ) te c h n iq u e o f K o b a y a s h i e t a l.(5). T h e H P L C s y s te m c o n s is te d o f a p u m p (J a s c o , P U 9 8 0 ), a U V d e te c to r w ith v a ria b le w a v e le n g th (J a s c o , U V 9 7 5 ), a R h e o d y n e v a lv e (R 7 7 2 5 ) a s a n in je c t io n u n it, a c o m p u tin g in te g ra to r (C a lib ra 3 8 6 P C ), a n d a re v e rs e d p h a s e C 1 8 c o lu m n p a c k e d w ith N u c le o s il 100 (le n g th 2 5 c m , in te rn a l d ia m e te r 4 m m , p a rtic le s iz e 5 p m ; M a c h e r e y -N a g e l). T h e m o b ile p h a s e w a s a c e t o n itr ile - 0 .0 5 M p h o s p h a te b u ffe r (p H = 8 .5 ; 3 0 :7 0 v /v ) a n d th e m ix tu re w a s filte re d a n d d e g a s s e d b e fo re u s e . S e p a ra tio n s w e re m a d e a t a m b ie n t te m p e ra tu r e w ith a flo w ra te of 1 .0 m l/m in . D e te c tio n w a s p e rfo rm e d a t a w a v e le n g th o f 3 0 2 n m . S t a t i s t i c s : T h e lin e a r ity o f th e a s s a y w a s e x a m in e d fo r o m e p r a z o le a t c o n c e n tr a tio n s ra n g in g fro m 3 0 -1 0 0 0 n g /m l in p la s m a . S ta n d a rd s a m p le s w e re p re p a re d b y a d d in g th e a n a ly te to d r u g - fr e e p la s m a a n d w e r e e x tr a c te d a s d e s c rib e d b y K o b a y a s h i e t al. (5). P e a k a re a s w e re m e a s u re d a n d th e c a lib ra tio n g ra p h w a s o b ta in e d fr o m th e le a s t- s q u a r e s lin e a r re g re s s io n . T h e re g re s s io n lin e w a s u s e d to c a lc u la te th e c o n c e n tr a tio n s o f th e re s p e c tiv e a n a ly te s in th e u n k n o w n s a m p le s . T h e in tra - a n d in te ra s s a y c o e ffic ie n ts o f v a ria tio n (C .V .) w e re < 2 0 % . T h e p e a k p la s m a c o n c e n tr a tio n (C max) a n d th e tim e to re a c h p e a k p la s m a c o n c e n tra tio n ( W ) w e re c a lc u la te d fro m th e a c tu a l o b s e rv e d p la s m a d a ta o f e a c h v o lu n te e r. T h e a re a u n d e r th e p la s m a o m e p r a z o le c o n c e n tr a tio n -tim e c u rv e (A U C 0.t) b y tr a p e z o id a l ru le a n d th e A U C t. „ b y d iv id in g th e la s t o b s e r v e d o m e p r a z o le c o n c e n tra tio n b y e lim in a tio n ra te c o n s ta n t. T h e d a ta a re e x p re s s e d a s m e a n ± S .E .M . a n d w e re a n a ly z e d s ta tis tic a lly b y th e S tu d e n t's p a ire d t- te s t.RESULTS
A ll th e s u b je c ts c o m p le te d th e s tu d y a n d no a d v e rs e e v e n ts w e re o b s e rv e d . T h e in d iv id u a l p la s m a c o n c e n tr a tio n - tim e p r o file s a fte r th e a d m in is t r a t io n o f e n te r ic - c o a t e d o m e p r a z o le c a p s u le s s h o w e d in te rin d iv id u a l v a ria tio n w ith b o th p re p a ra tio n s . In s o m e c a s e s , a s in g le p e a k w a s o b s e r v e d , w h e r e a s m u ltip e a k p r o file s o c c u rre d in o th e rs . T im e to th e e a rly p e a k s w a s 1-2 h a n d th o s e p e a k s w e re lo w e r in a m p litu d e th a n th e p e a k s re a c h e d a p p ro x im a te ly 4 .5 h a fte r th e a p p lic a tio n . F ig . 1 s h o w s th e m e a n p la s m a o m e p r a z o le c o n c e n tr a tio n o f th e v o lu n te e rs at d iffe r e n t tim e in te rv a ls a fte r a s in g le d o s e o f 20 m g o f p ro d u c t "A " a n d "B " a n d T a b le I s h o w s th e m e a n v a lu e s o f C max, A U C 0_„ a n d t max fo r b o th
Plasma concentration-time profile of a single dose of enteric coated omeprazole
F ig . l Plasma omeprazole concentrations (mean ± S.E.M.) at different time intervals after a single dose of 20 mg enteric-coated omeprazole capsules given 10-15 mins before breakfast in 12 healthy volunteers.
T a b l e I. C o m pa ra tive p h a rm a co kin etics a fte r a single oral dose of o m e p ra zo le (20 m g) in healthy volunteers. Values are e xp re sse d as m ean±S .E .M .
Parameters Product A Product B
Cmax (nQ/ml) 361 2±71 1 317.7±85.8
’ max (’’ ) 4,5±0.3 4.2±0.3
AUC g.^ (ng/ml.h) 961±303 980±322
p ro d u c ts . A ll o f th e s e p a ra m e te rs w e re n o t s ig n ific a n tly d iffe r e n t fro m e a c h o th e r.
W h e n th e re s u lts o b ta in e d fro m m a le a n d fe m a le s u b je c ts w e re re a n a ly z e d s e p a ra te ly , it w a s s e e n th a t th e m u ltip e a k p ro file w a s m o re fr e q u e n t a n d th e a m p litu d e s o f th e e a rly p e a k s w e re s ig n ific a n tly h ig h e r in fe m a le s u b je c ts (p < 0 .0 5 ; F ig s . 2 -4 ).
F ig .2 Median plasma omeprazole concentrations at different time Intervals after a single dose of 20 mg enteric-coated omeprazole capsules given 10-15 mins before breakfast in 6 healthy male volunteers.
F lg .3 Median plasma omeprazole concentrations at different time intervals after a single dose of 20 mg enteric-coated omeprazole capsules given 10-15 mins before breakfast in 6 healthy female volunteers.
F ig .4 The amplitude of the early omeprazole peak plasma concentration reached 1-2 hrs. after a single dose of 20 mg enteric-coated omeprazole capsules given 10-15 mins before breakfast in female (n=6) and male (n=6) healthy volunteers. *p<0.05 vs female subjects.
DISCUSSION
In th e p re s e n t s tu d y , th e a re a u n d e r th e p la s m a o m e p r a z o le - tim e c u r v e (A U C ) w a s s im ila r fo llo w in g b o th p ro d u c ts . A lth o u g h s lig h tly (b u t n o t s ig n ific a n tly ) h ig h e r C max v a lu e s w e re o b ta in e d w ith p ro d u c t "A ", p ro d u c t "A " a n d "B " m a y be c o n s id e re d to b e b io e q u iv a le n t s in c e th e d e g re e
Ece İskender, et al
o f s u p p re s s io n o f g a s tric a c id s e c re tio n w a s re p o rte d to b e c o rre la te d to th e A U C b u t n o t to th e p la s m a c o n c e n tra tio n a t a n y g iv e n tim e (4). T h e g re a t in te rs u b je c t v a ria b ility in A U C v a lu e s c a n be e x p la in e d b y 3 s u b je c ts b e in g o u tly e rs . T h o s e s u b je c ts (1 fe m a le a n d 2 m a le s ) h a d th e h ig h e s t A U C v a lu e s fo llo w in g b o th p ro d u c ts . T h e y m a y b e s lo w m e ta b o liz e rs o f o m e p ra z o le (6). T h e o m e p ra z o le d o s a g e re c o m m e n d e d in th e c lin ic a l p ro g r a m m e w a s to b e ta k e n b e fo re b re a k fa s t. A n d e rs s o n e t al. (6) re p o rte d th a t th e a m o u n t o f o m e p ra z o le a b s o rb e d w a s u n a ffe c te d b y w h e th e r th e c a p s u le s w e re ta k e n b e fo re o r a fte r b r e a k fa s t. T h e m u ltip e a k p la s m a c o n c e n tra tio n -tim e p ro file s e e n in th is s tu d y w a s s im ila r to th o s e re p o rte d b y A n d e rs s o n e t a l. (6) w h e n th e d ru g w a s g iv e n b e fo re b re a k fa s t a s in o u r c a s e . In te re s tin g ly , a lth o u g h th e in v e s tig a to rs d id n o t s tre s s th is , a s in g le p e a k p ro file w a s o b ta in e d w h e n o m e p r a z o le w a s ta k e n a fte r b r e a k fa s t. S in g le p e a k p r o file s w e re a ls o re p o rte d b y s e v e ra l o th e r in v e s tig a to rs w h e n th e y g a v e e n te r ic - c o a te d o m e p r a z o le p re p a r a tio n s 2 .5 -3 h rs. a fte r b re a k fa s t (7 -9 ). E n te ric c o a tin g is a c c e p te d to p r e v e n t th e g ra n u le s re le a s in g o m e p ra z o le u n til th e y re a c h th e in te s tin e a n d th e ra te o f g a s tric e m p ty in g d e te rm in e s th e tim e to a b s o rp tio n . T h e tim e to th e firs t d e te c ta b le p la s m a c o n c e n tra tio n w a s re p o rte d to b e s h o rte r a fte r th e d ru g g iv e n b e fo re b r e a k fa s t (6 ). T h e r e fo r e , th e e a r lie r o f th e o m e p ra z o le p e a k s in p la s m a m a y re p re s e n t th e o m e p ra z o le g ra n u le s le ft in th e s to m a c h b e fo re fo o d in g e s tio n . It s e e m s lik e ly th a t th e a rriv a l o f th e re m a in in g o m e p r a z o le g r a n u le s to th e in te s tin a l lu m e n w e re d e la y e d b y fo o d e a te n 10- 15 m in s, a fte r o m e p ra z o le . T h e in te re s tin g o b s e rv a tio n o f th is s tu d y w a s th e d iffe r e n c e b e tw e e n th e m a le a n d fe m a le s u b je c ts . It w a s s e e n th a t th e m u ltip e a k p ro file w a s m o re fre q u e n t a n d th e a m p litu d e s o f th e e a rly p e a k s w e re h ig h e r in fe m a le s u b je c ts . T h e d e s ig n o f th is s tu d y a n d th e n u m b e r o f s u b je c ts d o n o t a llo w u s to m a k e a n y s p e c u la tio n s o n th is fin d in g . F u rth e r p h a rm a c o k in e tic s tu d ie s in b o th h e a lth y v o lu n te e rs a n d p a tie n ts w ith p e p tic u lc e r d is e a s e a re n e e d e d to c le a r ify th e is s u e . F u r th e r m o r e , th e p o s s ib ility o f th e g e n d e r d iffe re n c e on th e s u p p re s s io n o f g a s tric a c id s e c r e tio n b y o m e p r a z o le m u s t a ls o b e in v e s tig a te d . A c k n o w le d g e m e n t : T h is s tu d y w a s s p o n s o re d b y İls a n İla ç la rı A .Ş ., Is ta n b u l, T u rk e y . T h e a u th o rs w is h to th a n k all th e v o lu n te e rs fo r p a rtic ip a tin g th e s tu d y .
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