R. L. AAMODT and W. F. RUMBLE
National Institutes of Health, Bethesda, MD 20205 ROBERT I. HENKIN
Georgetown University Medical Center, Center for Molecular Nutrition and Sensory Disorders, Washington, DC 20007
We have studied
using a detailed kinetic model and the SAAM27 computer program. Absorption of Zn-65 by 75 fast- ing normal volunteers was 65
±11% (mean± 1SD), range 40-86%). Absorption related to age (by decade) decreased linearly A=69.5-0.123Y (A=absorption, Y=age i n years), correlation coefficient(r)=-0.934.
Although mean absorption by women was higher (67±
2%, mean±1SEM) than that of men (63
±2%) this d i f -ference was not s t a t i s t i c a l l y significant (ANOVA or t-test for comparison of means). Absorption re- lated to age (by decade) was significantly less (p<0.05) for men than for women (paired t - t e s t ) . Three subjects who ate breakfast before receiving Zn-65 had significantly lower absorption (17.4%, range 9-31%) than fasting subjects. Although human zinc absorption decreased with age, the mechanism of this change i s unclear. Food decreases zinc absorption but specific food effects are not well defined.
Zinc metabolism i s a dynamic process which cannot be fully defined by any single static measurement. Since i t i s related i n part to absorption, zinc b i o a v a i l a b i l i t y can be reduced by abnormalities i n the gastrointestinal tract, i n transport ligands or substances i n the intestinal contents which interfere with zinc absorption. Bioavailability can also be affected by metabo- l i c defects which prevent zinc uptake or u t i l i z a t i o n after absorption and by several additional factors. Some of these additional factors have been considered by previous investigators and include age, sex, food and the i n i t i a l conditions under which bioavailability and metabolism were determined.
A number of processes related to absorption and metabolism
occur simultaneously following the ingestion of zinc (Figure 1).
NUTRITIONAL BIOAVAILABILITY OF ZINC
Intake
Fecal ExcretionI
•
Secretion Secretion
Blood Tissue Blood Tissue Pool Pools Absorption
and 1 Urinary reabsorption j excretion
Figure 1. A simple model illustrating some of the complex interactions involved in zinc absorption and metabolism. Following absorption, a fraction of the zinc goes directly into blood, another fraction passes first through the portal circulation and then into the systemic circulation. Some zinc is resecreted into the gastrointestinal tract, thereby becoming available for reabsorption. Activity in blood can exchange with tissue pools, be excreted in urine, or secreted back into the gastrointestinal tract.
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
A f r a c t i o n of the i n g e s t e d z i n c i s absorbed, but the r a t e of a b s o r p t i o n i s not c o n s t a n t throughout the g a s t r o i n t e s t i n a l t r a c t ( l ) . Some of the absorbed z i n c e n t e r s the s y s t e m i c c i r c u l a - t i o n d i r e c t l y , some e n t e r s the p o r t a l c i r c u l a t i o n f i r s t , then passes i n t o the g e n e r a l c i r c u l a t i o n , and some i s s e c r e t e d back i n t o the gut and i s then a v a i l a b l e f o r r e a b s o r p t i o n .
One e f f e c t i v e method of o b t a i n i n g i n f o r m a t i o n about z i n c metabolism i s the use of r a d i o a c t i v e t r a c e r s to study a b s o r p t i o n , k i n e t i c s and body d i s t r i b u t i o n f o l l o w i n g o r a l a d m i n i s t r a t i o n . Of course, as i n a l l cases i n which r a d i o n u c l i d e s a r e a d m i n i s t e r e d to human s u b j e c t s , the hazard of such a d m i n i s t r a t i o n must be c o n s i d e r e d and balanced a g a i n s t the v a l u e of i n f o r m a t i o n expected from the study. The a d m i n i s t e r e d a c t i v i t y s h o u l d be as low as p o s s i b l e c o n s i s t e n t w i t h o b t a i n i n g adequate measurements. The s t u d i e s r e p o r t e d here wer
proved p r o t o c o l s whic
of human s u b j e c t s and w i t h the informed consent of the p a r t i c i p a t i n g s u b j e c t s .
The f o l l o w i n g i s a summary of r e s u l t s of z i n c metabolism s t u d i e s of p a t i e n t s and normal v o l u n t e e r s c a r r i e d out over the past 10 y e a r s . I n i t i a l l y n e a r l y a l l the absorbed z i n c i s i n plasma, but i t I s r a p i d l y taken up by the l i v e r ( F i g u r e 2 ) . During the f i r s t 5 to 48 hours a p p r o x i m a t e l y 70% of the absorbed r a d i o a c t i v e z i n c t r a c e r goes to the l i v e r ( l ^ , 2 ^ , 3^). D u r i n g the next 50 days l i v e r z i n c decreases w h i l e Zn-65 a c t i v i t y i n the t h i g h ( p r i m a r i l y muscle z i n c ) i n c r e a s e s (3). Uptake i n the t h i g h appears to m i r r o r l o s s e s from the l i v e r u n t i l a f t e r about 100 days when b o t h have s i m i l a r a c t i v i t y and decrease at about the same r a t e . Red blood c e l l s b e g i n to take up z i n c r a p i d l y , w i t h a c t i v i t y appearing as e a r l y as 15 minutes a f t e r a d m i n i s t r a t i o n and i n c r e a s i n g t h e r e a f t e r to reach maximum v a l u e s 7 to 14 days l a t e r( 3 ) . T o t a l body r e t e n t i o n decreases r a p i d l y a t f i r s t as unabsorbed z i n c i s e x c r e t e d , then more s l o w l y( 3 ). A f t e r about 100 days a l l body compartments l o s e z i n c v e r y s l o w l y w i t h h a l f - times of approximately 400 days(3).
In order to understand these complex m e t a b o l i c i n t e r a c t i o n s more f u l l y and to maximize the i n f o r m a t i o n o b t a i n e d i n these s t u d i e s , we developed a d e t a i l e d k i n e t i c model of z i n c métabolisme,^). Modeling of the k i n e t i c data obtained from measurements of b i o l o g i c a l t r a c e r s by compartmental a n a l y s i s a l l o w s d e r i v a t i o n of i n f o r m a t i o n r e l a t e d not o n l y t o the t r a n - s i e n t dynamic p a t t e r n s of t r a c e r movements through the system, but a l s o i n f o r m a t i o n about the steady s t a t e p a t t e r n s of n a t i v e z i n c . T h i s approach p r o v i d e s d a t a f o r a b s o r p t i o n , a b s o r p t i o n r a t e s , t r a n s f e r r a t e s between compartments, z i n c masses i n the t o t a l body and i n d i v i d u a l compartments and minimum d a i l y r e q u i r e - ments. Data may be c o l l e c t e d w i t h o u t d i s r u p t i n g the normal l i v i n g p a t t e r n s of the s u b j e c t s and the d i f f i c u l t i e s and i n c o n - veniences of m e t a b o l i c wards can be a v o i d e d .
The i n i t i a l z i n c model was based upon averaged data f o r 17
NUTRITIONAL BIOAVAILABILITY OF ZINC
1 0 0 . 0 - 8 0 . 0 -
6 0 . 0 -
40.0 h
0 50 100 150 200 250 300 D A Y S A F T E R A D M I N I S T R A T I O N
Figure 2. Percentage of 65Zn activity present in liver (O) and thigh (Φ) areas of normal subjects measured by external y-ray detectors during a 350-day period after oral administration. Activity in the liver area increased rapidly during the period between 5 and 48 h to approximately 7Οψο of the absorbed activity (49% of administered activity), then decreased. Activity in the thigh area increased more slowly, reaching maximum values by about 50 days, then decreasing. A fter approxi
mately 100 days after administration both liver and thigh areas had similar activities and loss rates.
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
p a t i e n t s w i t h d e f e c t s of t a s t e and s m e l l g i v e n Zn-69m both o r a l l y and i n t r a v e n o u s l y two weeks a p a r t ( ^ ) . These data were analyzed u s i n g the SAAM27 computer program(4^ and a model f o r z i n c metabolism(l_) was d e r i v e d ( F i g u r e 3)· The compartmental model used a l l the k i n e t i c data obtained from Zn-69m a c t i v i t y i n plasma, red blood c e l l s , l i v e r and t h i g h as w e l l as s t a b l e z i n c parameters, i n c l u d i n g : d i e t a r y i n t a k e , serum l e v e l s and u r i n a r y c o n c e n t r a t i o n . These v a l u e s were used to o b t a i n the s i m p l e s t s e t of mathematical r e l a t i o n s h i p s t h a t would s a t i s f y a l l of the data c h a r a c t e r i s t i c s f o r each measurement time i n the study w h i l e remaining c o n s i s t e n t w i t h accepted concepts of z i n c metabolism.
D e s p i t e the s h o r t h a l f - t i m e of Zn-69m which l i m i t e d the d a t a c o l l e c t i o n p e r i o d such t h a t the model could o n l y a n a l y z e the r a p i d processes of z i n c metabolism ( a p p r o x i m a t e l y 10% of t o t a l body z i n c ) , a number o
d e r i v e d as shown i n Tabl
TABLE I .
FUNDAMENTAL STEADY STATE ZINC PARAMETERS DERIVED FROM THE Zn-69m MODEL.
PARAMETER MEASURED CALCULATED NORMAL
VALUE VALUE VALUE
Plasma z i n c c o n c e n t r a t i o n (ug/ml) 0.90 1.07 1.0 D a i l y plasma z i n c i n t a k e (mg/day)
—
2.7—
Red c e l l z i n c c o n c e n t r a t i o n (ug/ml)
—
21.6 14.4Blood z i n c i n c e l l s (%)
—
92 75-88L i v e r z i n c c o n c e n t r a t i o n (ug/ml)
—
69.5 55-76U r i n a r y z i n c e x c r e t i o n (mg/day) 0.72 0.72 0.3-0.6
D a i l y z i n c i n t a k e (mg/day)
—
7.3—
A b s o r p t i o n (%) -mmm 37
—
The model a l s o c o n s i d e r e d the a b s o r p t i o n process ( F i g u r e 4) as o c c u r r i n g i n a s e r i e s of compartments w i t h outputs to plasma, red blood c e l l s and l i v e r ( l ) . The model thus a l l o w e d the d e f i n i - t i o n of a b s o r p t i o n as a k i n e t i c process and the separate con- s i d e r a t i o n of d i f f e r e n t a s p e c t s of t h i s process (such as the f r a c t i o n of absorbed z i n c which e n t e r s d i r e c t l y i n t o plasma and changes i n a b s o r p t i o n r a t e as a f u n c t i o n of time) from which a b s o r p t i o n i n v a r i o u s p a r t s of the gut c o u l d be o b t a i n e d ( 1 ) .
Because the s h o r t h a l f - t i m e of Zn-69m l i m i t e d these s t u d i e s to the e a r l y phases of z i n c metabolism, they were c o n t i n u e d w i t h the l o n g e r l i v e d n u c l i d e Zn-65(3). T h i s n u c l i d e a l l o w e d the development of an extended model of z i n c metabolism(5^) which i n c l u d e d data f o r both r a p i d and slower p r o c e s s e s . T h i s model was d i s c u s s e d i n d e t a i l i n r e f e r e n c e s 5 and 6 and w i l l be d e v e l -
OTHER TISSUES Figure 3. This kinetic model for zinc in humans was based on averaged data obtained following oral and i.v. administration of
69m Zn to 17 patients with abnormalities of taste and smell. The compartmental model used all kinetic data from
69m Zn activity in plasma, red blood cells, urine, liver, and thigh as well as stable zinc parameters, including dietary intake, serum, and urinary concentra- tion. The SA AM 27 computer program was used to obtain the simplest set of mathematical relation- ships that would satisfy the data characteristics for each measurement time in the study and remain consistent with accepted concepts of zinc metabolism. Although the short physical half-life of
69m Zn limited the data collection period, this model allowed for analysis of the rapid phases of zinc metabolism (about 10% of total body zinc) and derivation of a number of fundamental steady state parameters (see Table I).
In Nutritional Bioavailability of Zinc; Inglett, G.;
ACS Symposium Series; American Chemical Society: Washington, DC, 1983.