60P
A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR ABSORPTION OF ORAL PARACETAMOL IN MAN J,A.
Clements, W.S.
Nimmo, R . C .
Heading
& L.F.
Prescott
Department of Pharmacy, Heriot-Watt U n i v e r s i t y , and Department of T h e r a p e u t i c s C l i n i c a l Pharmacology, Royal I n f i r m a r y , Edinburgh
(1
I n c o n v e n t i o n a l p h a r m a c o k i n e t i c models o f drug a b s o r p t i o n o f o r a l l y - a d m i n i s t e r e d p r e p a r a t i o n s t h e g a s t r o i n t e s t i n a l t r a c t i s commonly t r e a t e d a s a s i n g l e e n t i t y . T h i s i s c l e a r l y a t v a r i a n c e w i t h t h e p h y s i o l o g i c a l s t r u c t u r e o f the g a s t r o i n t e s t i n a l tract. and r e c e n t s t u d i e s have shown t h a t g a s t r i c emptying r a t e i s an i m p o r t a n t d e t e r m i n a n t of a b s o r p t i o n of d r u g s such a s p a r a c e t a m o l (Nimmo and o t h e r s , 1975). W e p r o p o s e a model t o d e s c r i b e the k i n e t i c s o f a b s o r p t i o n o f o r a l l y - a d m i n i s t e r e d p a r a c e t a m o l i n man w i t h s e p a r a t e compartments r e p r e s e n t i n g the stomach and s m a l l intestine. Absorption ( f i r s t - o r d e r ) w a s assumed t o o c c u r o n l y from the s m a l l i n t e s t i n e w i t h s u b s e q u e n t d i s t r i b u t i o n i n t o c o n v e n t i o n a l c e n t r a l and p e r i p h e r a l body compartments.
p a r a c e t a m o l s o l u t i o n (20mg/kg) c o n t a i n i n g 113mIn d i e t h y l t r i a m i n e p e n t a a c e t i c a c i d (DTPA) (300pCi) a s a non-absorbable i s o t o p i c marker w a s i n g e s t e d by h e a l t h y f a s t i n g s u b j e c t s . The g a s t r i c emptying p a t t e r n w a s o b t a i n e d from t h e s e r i a l s c i n t i s c a n s of t h e abdomen (Heading and o t h e r s , 1 9 7 1 ) . F r e q u e n t blood samples w e r e t a k e n c o n c u r r e n t l y and p a r a c e t a m o l c o n c e n t r a t i o n s i n plasma were measured by g . 1 . c . ( P r e s c o t t , 1 9 7 1 ) . I n r e p e a t s t u d i e s i n some s u b j e c t s p e t h i d i n e (150mg) o r p e n t a z o c i n e (60mg) was g i v e n i n t r a m u s c u l a r l y 30 min p r i o r t o i n g e s t i n g t h e p a r a c e t a m o l and i s o t o p e s o l u t i o n . Only 6 of 19 s t u d i e s showed a s i n g l e monoexponential g a s t r i c emptying p a t t e r n (Type I ) . In e i g h t s t u d i e s t h e r e was a v e r y f a s t i n i t i a l emptying of t h e s o l u t i o n f o l l o w e d by monoe x p o n e n t i a l emptying of the remainder (Type XI). O t h e r s t u d i e s showed two p e r i o d s o f monoexponential emptying s e p a r a t e d by a q u i e s c e n t i n t e r v a l (Type 111). Plasma paracetamol c o n c e n t r a t i o n d a t a were a n a l y s e d by t h e proposed model and (where p o s s i b l e ) by t h e c o n v e n t i o n a l model u s i n g n o n - l i n e a r o p t i m i s a t i o n (Nelder & Mead, 1 9 6 5 ) . I n a l l c a s e s t h e proposed model gave good agreement between measured and c a l c u l a t e d v a l u e s , and y i e l d e d an estimate o f t h e r a t e c o n s t a n t (KA*) f o r a b s o r p t i o n from t h e small i n t e s t i n e ; t h e mean h a l f - t i m e f o r a b s o r p t i o n was 6.8 2 0.9 (5.d.) mins. O v e r a l l , t h e r e was no c o r r e l a t i o n between t h e g a s t r i c emptying r a t e c o n s t a n t (Q) d u r i n g the e x p o n e n t i a l p h a s e and t h e a p p a r e n t a b s o r p t i o n r a t e c o n s t a n t (KA) f o r t h e c o n v e n t i o n a l model ( F i g u r e 1 ) . However, t h e s e v a r i a b l e s were a p p r o x i m a t e l y e q u a l i n v a l u e where Type I emptying w a s o b s e r v e d . A s e x p e c t e d KA* w a s l a r g e r t h a n e i t h e r KA o r KG and t h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t The a p p a r e n t a b s o r p t i o n r a t e c o n s t a n t KA i s c o r r e l a t i o n between KA* and K A . t h e r e f o r e a h y b r i d c o n s t a n t and c a n n o t be used t o c a l c u l a t e e i t h e r KA* o r KG. Heading, R.C., T o t h i l l , P. and o t h e r s ( 1 9 7 1 ) . Gut 12 611-615. N e l d e r , J.A. & Mead, R . ( 1 9 6 5 ) . Comput.J., 7 308-313. Nimmo, W.S., Heading, R.C. and o t h e r s ( 1 9 7 5 ) . B r . J. C l i n Pharmac., 2 509-513. P r e s c o t t , L.F. ( 1 9 7 1 ) . J . Pharm. Pharmac., 23 111-115.
r A
F i g . 1. Apparent a b s o r p t i o n r a t e c o n s t a n t (KA) vs. g a s t r i c emptying r a t e c o n s t a n t (KG) f o r Type I (A) and Type I1 (A) emptying p a t t e r n s .
A
0.06. KG 0.04.
A
0.02
0:04
OJ.O6
A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR ABSORPTION OF ORAL PARACETAMOL IN MAN J,A.
Clements, W.S.
Nimmo, R . C .
Heading
& L.F.
Prescott
Department of Pharmacy, Heriot-Watt U n i v e r s i t y , and Department of T h e r a p e u t i c s C l i n i c a l Pharmacology, Royal I n f i r m a r y , Edinburgh
(1
I n c o n v e n t i o n a l p h a r m a c o k i n e t i c models o f drug a b s o r p t i o n o f o r a l l y - a d m i n i s t e r e d p r e p a r a t i o n s t h e g a s t r o i n t e s t i n a l t r a c t i s commonly t r e a t e d a s a s i n g l e e n t i t y . T h i s i s c l e a r l y a t v a r i a n c e w i t h t h e p h y s i o l o g i c a l s t r u c t u r e o f the g a s t r o i n t e s t i n a l tract. and r e c e n t s t u d i e s have shown t h a t g a s t r i c emptying r a t e i s an i m p o r t a n t d e t e r m i n a n t of a b s o r p t i o n of d r u g s such a s p a r a c e t a m o l (Nimmo and o t h e r s , 1975). W e p r o p o s e a model t o d e s c r i b e the k i n e t i c s o f a b s o r p t i o n o f o r a l l y - a d m i n i s t e r e d p a r a c e t a m o l i n man w i t h s e p a r a t e compartments r e p r e s e n t i n g the stomach and s m a l l intestine. Absorption ( f i r s t - o r d e r ) w a s assumed t o o c c u r o n l y from the s m a l l i n t e s t i n e w i t h s u b s e q u e n t d i s t r i b u t i o n i n t o c o n v e n t i o n a l c e n t r a l and p e r i p h e r a l body compartments.
p a r a c e t a m o l s o l u t i o n (20mg/kg) c o n t a i n i n g 113mIn d i e t h y l t r i a m i n e p e n t a a c e t i c a c i d (DTPA) (300pCi) a s a non-absorbable i s o t o p i c marker w a s i n g e s t e d by h e a l t h y f a s t i n g s u b j e c t s . The g a s t r i c emptying p a t t e r n w a s o b t a i n e d from t h e s e r i a l s c i n t i s c a n s of t h e abdomen (Heading and o t h e r s , 1 9 7 1 ) . F r e q u e n t blood samples w e r e t a k e n c o n c u r r e n t l y and p a r a c e t a m o l c o n c e n t r a t i o n s i n plasma were measured by g . 1 . c . ( P r e s c o t t , 1 9 7 1 ) . I n r e p e a t s t u d i e s i n some s u b j e c t s p e t h i d i n e (150mg) o r p e n t a z o c i n e (60mg) was g i v e n i n t r a m u s c u l a r l y 30 min p r i o r t o i n g e s t i n g t h e p a r a c e t a m o l and i s o t o p e s o l u t i o n . Only 6 of 19 s t u d i e s showed a s i n g l e monoexponential g a s t r i c emptying p a t t e r n (Type I ) . In e i g h t s t u d i e s t h e r e was a v e r y f a s t i n i t i a l emptying of t h e s o l u t i o n f o l l o w e d by monoe x p o n e n t i a l emptying of the remainder (Type XI). O t h e r s t u d i e s showed two p e r i o d s o f monoexponential emptying s e p a r a t e d by a q u i e s c e n t i n t e r v a l (Type 111). Plasma paracetamol c o n c e n t r a t i o n d a t a were a n a l y s e d by t h e proposed model and (where p o s s i b l e ) by t h e c o n v e n t i o n a l model u s i n g n o n - l i n e a r o p t i m i s a t i o n (Nelder & Mead, 1 9 6 5 ) . I n a l l c a s e s t h e proposed model gave good agreement between measured and c a l c u l a t e d v a l u e s , and y i e l d e d an estimate o f t h e r a t e c o n s t a n t (KA*) f o r a b s o r p t i o n from t h e small i n t e s t i n e ; t h e mean h a l f - t i m e f o r a b s o r p t i o n was 6.8 2 0.9 (5.d.) mins. O v e r a l l , t h e r e was no c o r r e l a t i o n between t h e g a s t r i c emptying r a t e c o n s t a n t (Q) d u r i n g the e x p o n e n t i a l p h a s e and t h e a p p a r e n t a b s o r p t i o n r a t e c o n s t a n t (KA) f o r t h e c o n v e n t i o n a l model ( F i g u r e 1 ) . However, t h e s e v a r i a b l e s were a p p r o x i m a t e l y e q u a l i n v a l u e where Type I emptying w a s o b s e r v e d . A s e x p e c t e d KA* w a s l a r g e r t h a n e i t h e r KA o r KG and t h e r e was no s t a t i s t i c a l l y s i g n i f i c a n t The a p p a r e n t a b s o r p t i o n r a t e c o n s t a n t KA i s c o r r e l a t i o n between KA* and K A . t h e r e f o r e a h y b r i d c o n s t a n t and c a n n o t be used t o c a l c u l a t e e i t h e r KA* o r KG. Heading, R.C., T o t h i l l , P. and o t h e r s ( 1 9 7 1 ) . Gut 12 611-615. N e l d e r , J.A. & Mead, R . ( 1 9 6 5 ) . Comput.J., 7 308-313. Nimmo, W.S., Heading, R.C. and o t h e r s ( 1 9 7 5 ) . B r . J. C l i n Pharmac., 2 509-513. P r e s c o t t , L.F. ( 1 9 7 1 ) . J . Pharm. Pharmac., 23 111-115.
r A
F i g . 1. Apparent a b s o r p t i o n r a t e c o n s t a n t (KA) vs. g a s t r i c emptying r a t e c o n s t a n t (KG) f o r Type I (A) and Type I1 (A) emptying p a t t e r n s .
A
0.06. KG 0.04.
A
0.02
0:04
OJ.O6
