Europ.J.clin.Pharmacol. 9, 49-55 (1975) © by Springer-Verlag 1975

Absorption of Digoxin in Infants G. Wet~ell and K.-E. Andersson Departments Sweden Received:

of Paediatrics

February

18,

and Clinical Pharmacology,

1975, accepted:

April

11,

University

Hospital,

Lund,

1975

sun~ary. The bioavailability of digoxin in solution was studied in 4 newborn infants with heart failure. Serum digoxin concentrations were determined by radioimmunoassay using 125I. Bioavailability was estimated by comparison of the areas under the 8-h serum concehtration curves (8-h AUC) after intravenous and oral administration of the glycoside. After oral administration of digoxin (I/4 of the digitalizing dose, 0.05 mg/kg bw), peak serum values of 2.3 - 4.4 ng/ml were reached within 30-90 min. After intravenous administration of the same amount of the glycoside, there was a rapid decrease in serum concentration during the first 2 h, and after about 4 h the serum concentration curves paralled those obtained after oral dosing. Based on within subject comparison of intravenous and oral 8-h AUC's, the mean bioavailability of digoxin was estimated to be 72 per cent (range 52 - 79 per cent). It was concluded that digoxin in solution, given to infants with mild to moderate heart failure, is well absorbed and biologically available to the same extent as in adults.

Key words: Digoxin, infants.

serum concentration,

area c o m p a r i s o n ,

It is generally held that paediatric patients in congestive heart failure need larger doses of digoxin (on a mg/kg basis) than adults to obtain a therapeutic effect (Neill, 1965; Rutkowski, Cohen and Doyle, 1973). The higher digoxin requirements in infants and children have been attributed to differences in the pharmacokinetics of the glycoside between the age groups (Rutkowski, Cohen and Doyle, 1973); for example agedependent differences in tissue f i x a t i o ~ renal excretion and intestinal absorption of digoxin have been discussed (Andersson, Bertler and Wettrell, 1975; Huffman and Kauffman, 1973; Iisalo and Dahl, 1974; Krausula eta!., 1972; Wettrell et ai.,1974). In adults, the gastrointestinal absorption of digoxin given in solution, amounts to 65 to 80 per cent (Greenblatt

et ai.,1973;

absorption,

radioimmunoassay,

Huffman, Manion and A z a r n o f ~ 1974; Nyberg, Andersson and Bertler, 1974; Wagner et al., 1973). In infants with severe congestive heart failure, comparison of the clinical effects of oral and intravenous digoxin therapy suggested that absorption was only 20 - 30 per cent (D~hlemann and B~hlmeyer, 1972). On the other hand, studies using tritiated digoxin in infants have shown almost complete gastrointestinal absorption (Hernandez et ai.,1969), and values in the same range as in adults (Doherty, 1968). According to the plasma levels of digoxin, infants on oral maintenance therapy with digoxin appeared to absorb the glycoside at least as well as adults (Larese and Mirkin, 1974). The absorption of digoxin by infants with heart failure has been examined by

50 comparison of the areas under the 8-h serum concentration curves found after oral and intravenous administration of the glycoside. Radioimmunoassay using 125I-label was employed to estimate serum digoxin concentrations.

MATERIAL

AND METHODS

Patients

Four patients, aged 2 - 33 days, were studied, all of w h o m had been full-term babies. Three of the patients had the diagnosis of congenital cardiac malformation and mild to moderate congestive heart failure. One neonate with hyperbilirubinaemia due to rhesus incompatability showed moderate heart failure after exchange transfusion. Clinical details about the infants have been given in Table I. Drug administration

Commercial preparations of digoxin were used for intravenous (Lanacrist solution for injection, AB Draco, Sweden) and oral (Lanoxin paediatric solution, Burr o u g h s - W e l l c o m e L t d . , United Kingdom) administration. The intravenous solution contained 250 ~g of digoxin/ml. Before injection, the solution was diluted 1:10 with physiologic saline. The oral preparation contained 0.05 mg of digoxin/ml in an 11 per cent alcoholic solution. At the start of the sampling period each patient received a single dose of digoxin, calculated to be one quarter of the digitalizing dose, 0.05 mg/kg bw; individual doses have been shown in Table I. In Patients I, 2, and 3, the first dose was injected via an umbilical vein catheter over a 2 to 3 minute period, during continuous electrocardiographic monitoring. Patient 4 received the first dose of digoxin orally. Due to diagnostic uncertainty and improvement in the clinical condition of the patients, digoxin therapy was then discontinued. After at least four days, the same dose of digoxin was given again, because of the clinical condition of the patients. Patients I, 2 and 3 received it orally and Patient 4 intravenously. No food was supplied for 2 hours before and after oral intake of the glycoside. For oral administration the digoxin solution was given via a feeding tube into the stomach, and immediately afterwards the tube was flushed with 2 ml physiologic saline. Patients receiving parenteral digoxin were not fasted.

Samples

Capillary blood was collected in Eppendorf tubes. Specimens from Pats. I, 2 and 3 were obtained via umbilical artery catheters during the first period of investigation. Blood was collected 15, 30, 60, 90 and 120 min, and 3, 4, 5, 6 and 8 h after administration of digoxin; individual sampling schedules have been listed in Table 2. In all cases a 24hour urine collection in a bag (Hollister Inc., USA) was started at the time when digoxin was administered intravenously. Digoxin Assay

Serum and urine digoxin analyses were performed with a commercial radioimmunoassay kit (Schwarz/Mann, Orangeburg, New York, USA) which uses 125I-digoxin as the tracer. Only 50 ~i aliquots of serum were required for each analysis. Digoxin concentrations in urine were also determined by a 86Rb uptake inhibition method (Bert!er and Redfors, 1970; Wettrell et al., 1974). Evaluation of the Method

Venous blood samples were obtained from 112 in-patients on maintenance digoxin therapy and the serum digoxin levels assayed radio-immunologically using both 3H (Schwarz/Mann) and 125I labels. C a p i ~ lary samples were collected at the same time from 22 of the patients and these specimens were assayed for digoxin by the 1251-technique. Conventional statistical methods were used to compare the assay methods and sampling procedures. The statistical significance of paired comparison between two sample means was evaluated by Student's t-test. Pharmacokinetic Analysis

In order to estimate the quantity of digoxin absorbed, areas under the serum concentrations curves (AUC) were calculated for each patient after intravenous and oral administration of the glycoside. The areas were estimated by the trapezoidal rule. The fraction of the dose absorbed, F, was calculated as: AUC oral F= ....... AUC. l.v. The measurements depend upon the assumption that elimination does not vary with the route of administration (Jusko, 1972).

51

Table

i. C l i n i c a l

Pat. no.

Sex

I

details

of the 4 p a t i e n t s

given digoxin

intravenously

Age, days

R o u t e of administration

Dosage mg

mg/kg bw

M

~ 6

intravenous oral

0.040

0.O11

P o s t - a s p h y x i a syndrome with e n l a r g e m e n t of the h e a r t

2

F

3

intravenous oral

0.038

0.014

Suspected transposition of the g r e a t vessels; a s p h y x i a syndrome

3

M

~ 6

intravenous oral

0.050

0.025

Hyperbilirubinaemia (Rh incompatability)

4

F

23 33

oral intravenous

0.040

O.O~i

Coarctation

Table

2. S e r u m

digoxin

concentrations

after

Clinical

and orally

intravenous

diagnosis

of the a o r t a

a n d oral d o s i n g

Pat. no.

R o u t e of administration

O. 25

Serum concentration O. 5 1 1.5 2

i

intravenous

28.5

9.6

2.7

I .6

1.3

1.O

0.5

-

-

0.3

oral

-

I.O

2.0

2.3

I .6

I .4

i .5

-

1.0

0.6

intravenous

-

8.2

4.5

3. O

2.3

I. 9

i. 2

-

-

I. 0

at hours p o s t - d o s i n g 4 5 6 8

oral

-

3.3

4.4

4.1

3.1

i .6

-

-

-

1.2

intravenous

-

8.5

5.2

3.5

2. i

i. 7

-

1.4

-

i. 2

oral

-

2.4

3.5

3.9

3.7

2.4

-

1.5

-

1.2

intravenous

6.6

4.1

2.O

1.4

I.i

1.0

0.6

-

0.5

O.5

oral

-

3.7

3.5

3.0

1.7

i.O

0.9

-

-

0.5

Table 3. A r e a s u n d e r the serum c o n c e n t r a t i o n curves d i g o x i n a n d d a i l y u r i n a r y e x c r e t i o n of digoxin Pat. no.

(ng/ml) 3

Route of administration

A U C (ng/ml x hour)

Absorption (per cent)

8-h

(AUC),

absorption

of

U r i n a r y excretion, p e r cent of ad-

Urine volume,

ministered

ml

dose

1

intravenous oral

19.3 iO.i

52

13 _

160 _

2

intravenous oral

20.2 16.0

79

13 _

162 _

3

intravenous oral

21.5 16.8

78

14

160

4

intravenous oral

13.4 10.6

79

25

166

52 RESULTS The i n d i v i d u a l serum d i g o x i n values during the first 8 h after single oral and intravenous doses of the glycoside are shown in Figs. I and 2, and in Table 2. After oral administration, peak serum values of 2.3 - 4.4 ng/ml were found w i t h i n 30 - 90 min (Fig. I). In one patient (no. 1), there was a second, slight increase in serum c o n c e n t r a t i o n between the 3rd and 6th h after dosing. After intravenous injection of digoxin, the glycoside d i s a p p e a r e d rapidly from blood for the first 2 h (Fig. 2), and then more slowly. 8 h after administration serum levels b e t w e e n 0.3 and 1.2 ng/ml were found. In three of the patients (nos. I, 2 and 4), there was a slight d e v i a t i o n from the e x p e c t e d slope of the serum c o n c e n t r a t i o n curve b e t w e e n the 2nd and 4th h after the injection. The mean area under the e i g h t - h o u r serum c o n c e n t r a t i o n curve was 13.4 (range 10.1 - 16.8) ng/ml x h after oral d o s i n g (Table 3). W i t h i n subject comp a r i s o n of this area w i t h that calculated after intravenous a d m i n i s t r a t i o n showed that the oral solution area averaged 72 per cent (range 52-79 per cent) of the intravenous area. U r i n a r y e x c r e t i o n of d i g o x i n during the first 24 h after p a r e n t e r a l administration was 13 - 25 per cent of the dose given (Table 3). During this period, the n e w b o r n patients (No. I, 2, and 3) excreted a p p r o x i m a t e l y half the amounts of digoxin found in the urine of the older p a t i e n t (No. 4). There were no obvious d i f f e r e n c e s b e t w e e n urinary digoxin e x c r e t i o n s m e a s u r e d by the 86Rb and radioimmunoassay (125I) techniques. D i g o x i n c o n c e n t r a t i o n s m e a s u r e d both by the 3H and 125I-label m e t h o d s were compared in 112 split venous samples from in-patients. The d i s t r i b u t i o n of the values in the c o n c e n t r a t i o n range 0.4 - 6.1 ng/ml is shown in Fig. 3. The d i f f e r e n c e s o b s e r v e d were not stat i s t i c a l l y s i g n i f i c a n t (p>O.O5). The 1 2 5 I - d i g o x i n assay was also used to compare the c o n c e n t r a t i o n s found in blood o b t a i n e d by simultaneous c a p i l l a r y and venous sampling in 22 adult patients. The results are p l o t t e d in Fig. 4; there 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 deviation from the line of equality (p>O.05).

DISCUSSION P h a r m a c o k i n e t i c studies in neonates and infants are d i f f i c u l t to p e r f o r m as repeated d e t e r m i n a t i o n s of serum concentration are necessary. A reliable micro-

m e t h o d was required that w o u l d p e r m i t e s t i m a t i o n of d i g o x i n in c a p i l l a r y b l o o d In fact, it was a p r e - r e q u i s i t e for the p r e s e n t investigation. R a d i o i m m u n o a s s a y of d i g o x i n using 125I as the tracer, which required only 50 ~i of serum for a single analysis, has p r e v i o u s l y been d e m o n s t r a t e d to be a sensitive and reliable assay method, as good as that involving t r i t i a t e d d i g o x i n (Gutcho, Mc Carter and Rapun, 1973; H o r g a n and Ridey, 1973). This was also c o n f i r m e d in the p r e s e n t study by c o m p a r i s o n of the two assays. Furthermore, the p r e s e n t results showed good a g r e e m e n t b e t w e e n d i g o x i n c o n c e n t r a t i o n s in s i m u l t a n e o u s venous and c a p i l l a r y blood samples. This evidence was important, as c a p i l l a r y samples were used to follow the changes in serum d i g o x i n c o n c e n t r a t i o n after adm i n i s t r a t i o n of the glycoside by different routes. A l t h o u g h c u m u l a t i v e urinary e x c r e t i o n of d i g o x i n is p r o b a b l y the best means to assess the extent of a b s o r p t i o n (Greenblatt et al., 1973; Huffman, M a n i o n and Azarnoff, 1974), this m e t h o d is unp r a c t i c a l and d i f f i c u l t to use in neonates and infants. The low renal excretion of d i g o x i n in neonates (Iisalo and Dahl, 1974, Wettrell et al., 1974) as compared w i t h adults may reduce the value of the urine analysis in this agegroup. Therefore, the areas under the serum c o n c e n t r a t i o n curves after single intravenous and oral doses of the glycoside were used in the p r e s e n t study as an index of b i o a v a i l a b i l i t y . D e t e r m i n a t i o n of serum digoxin concentrations for long periods after a single dose are d i f f i c u l t to perform, because the level rapidly decreases, and the lower limit of s e n s i t i v i t y of the 125I assay is 0.2 ng/ml (Horgan and Ridey, 1973). In adults, it can be assumed that the g a s t r o i n t e s t i n a l absorption of digoxin is complete w i t h i n 8 h (Nyberg, A n d e r s s o n and Bertler, 1974). The p r e s e n t data suggest this was valid also in infants, as the rate of absorption a p p e a r e d to be similar. None the less, area c o m p a r i s o n using a sampling p e r i o d of 8 h may imply a certain undere s t i m a t i o n of the bioavailability. A c c o r d i n g to the data of N y b e r g et al. (1974), the u n d e r e s t i m a t e can be calc u l a t e d to be less than 10 per cent for a solution of digoxin. Thus, as the u n d e r e s t i m a t e seems to be small, and as a good c o r r e l a t i o n has been found between 8-h AUC and c u m u l a t i v e u r i n a r y excretion (Fleckenstein, K r o e n i n g and Weintraub, 1974; G r e e n b l a t t et al., 1973), m e a s u r e m e n t s of 8-h AUC were c o n s i d e r e d suitable for the study of a b s o r p t i o n in the p r e s e n t patients.

53

Digoxin, ng/ml 7- 125j

I Digoxin,

6-



ng/ml 5 5-





4-

2 • :ee/~

31

--7~

' 1

[ 2

T 3

r 4

I~' 5

~ --7 6 7

~ 8 Time,h

Fig. I. E i g h t h o u r s e r u m d i g o x i n c o n c e n t r a t i o n c u r v e s in 4 i n f a n t s a f t e r a d m i n i s t r a t i o n of a s i n g l e oral d o s e of d i g o x i n

T

1

U----

2

]

~

l

4

5

3H l

l

6

7

Digoxin, ng/ml

Fig. 3. R e l a t i o n s h i p b e t w e e n s e r u m d i g o x i n conc e n t r a t i o n s (venous b l o o d samples) d e t e r m i n e d b y 125I and 3H r a d i o i m m u n o a s s a y in 112 inp a t i e n t s . R e g r e s s i o n e q u a t i o n and c o r r e l a t i o n c o e f f i c i e n t : y = 1.19x - 0.26; r = 0 . 9 0

Digoxin. ng/ml

Digoxin, ng/ml 4.0- venous

10-

sampling 9-

3,5-

8-

3.0-

7-

2,5-

6543-

i

2.01.51.00.5-

../ / ~

capillary sampling

2-

[-- f 0.5 1,0

4& --

[ t

~

...... 4 ------7-2 3 4

....I 5

- - 7

i

6

7

- 7 ~

8 Time, h

Fig. 2. E i g h t h o u r s e r u m d i g o x i n c o n c e n t r a t i o n c u r v e s in 4 i n f a n t s a f t e r a d m i n i s t r a t i o n of a s i n g l e i n t r a v e n o u s dose of d i g o x i n

I

1.5

---7- ....... I - -

2.0

2.5

l

3.0

3!5 - - ~ 4.0 Digoxin, ng/ml

Fig. 4. R e l a t i o n s h i p b e t w e e n s e r u m d i g o x i n conc e n t r a t i o n s in s i m u l t a n e o u s v e n o u s a n d c a p i l l a r y b l o o d s a m p l e s from 22 a d u l t p a t i e n t s e s t i m a t e d by 125I-radioimmunoassay. Regression equation a n d c o r r e l a t i o n c o e f f i c i e n t : y = 0 . 9 6 x - O.12; r = 0.96

54 Based on w i t h i n - s u b j e c t comparisons of the 8-h AUC's after intravenous and oral administration, the p r e s e n t results showed that the b i o a v a i l a b i l i t y of digoxin elixir given orally to neonates and infants was a p p r o x i m a t e l y 72 per cent (range 52 - 79 per cent), a value in good agreement w i t h that reported by G r e e n b l a t t et al. (1973) for adults. However, it should be noted that the time intervals b e t w e e n intravenous and oral a d m i n i s t r a t i o n of d i g o x i n to the neonates (No. I, 2, and 3) were short, and probably did not allow complete elimination of the glycoside. It is possible, therefore, that residual body stores of digoxin at the time of a d m i n i s t r a t i o n of the second, oral dose could have led to larger AUC's, and so to o v e r e s t i m a t i o n of bioavailability. On the other hand, such an o v e r e s t i m a t e might well be c o u n t e r a c t e d by the increase in renal function during the first w e e k of life, which w o u l d lead to more rapid eliminati'on of the g l y c o s i d e and to a smaller AUC. Taking these potential sources of error into account, and also the small number of infants in the study, the present results still suggest that there was no significant d i f f e r e n c e b e t w e e n infants and adults in the a b s o r p t i o n of digoxin. Hernandez et al. (1969) reached a similar c o n c l u s i o n after studying the a b s o r p t i o n of t r i t i a t e d digoxin in infants. They found that the degree of absorption in their patients was in the same range as that reported for adults by other authors using the same technique (Doherty, 1968; Marcus, Kapadia and Kapadia, 1964). D 6 h l e m a n n and BHhlmeyer (1972) e v a l u a t e d the relative efficacy of digoxin given orally and i n t r a v e n o u s l y to infants in heart failure, and e s t i m a t e d that only 20-30% of an oral dose was absorbed. Their result may be e x p l a i n e d by the use of clinical p a r a m e t e r s to estimate absorption, and also because they e v a l u a t e d infants with severe cardiac insufficiency. It has been d e m o n s t r a t e d in adults (Oliver, Taxman and Frederickson, 1973) that congestive heart failure can impair the a b s o r p t i o n of digoxin, and that absorption becomes normal when the failure has been compensated. A complete d e f i n i t i o n of b i o a v a i l ability would include a s s e s s m e n t not only of the extent but also of the rate of absorption. Peak serum c o n c e n t r a t i o n s in the p r e s e n t patients in the fasting state were found w i t h i n 30-90 min after

a d m i n i s t r a t i o n of a single dose of d i g o x i n solution. Adults under similar conditions have shown a similar time course of changes in serum concentration (Greenblatt et al., 1973; Redfors, 1972). Hernandez et al. (1969) r e p o r t e d peak c o n c e n t r a t i o n s in p e r i p h e r a l blood I - 3 h after oral a d m i n i s t r a t i o n of a solution of t r i t i a t e d d i g o x i n to infants. In that study, the delay in peak value might have been due to the use of m e a s u r e m e n t s made after food intake, as there is no information about feeding in the report. However, for d e t e r m i n a t i o n of b i o l o g i c a l l y available amount from digoxin preparations, the time to attain the peak serum c o n c e n t r a t i o n is of secondary importance, as it does not reflect the c o m p l e t e n e s s of a b s o r p t i o n (Greenblatt et al., 1973; Sanchet et al., 1973). In the p r e s e n t study no attempt was made to assess b i o a v a i l a b i l i t y from u r i n a r y e x c r e t i o n of the glycoside. However, the few results a v a i l a b l e about urinary e x c r e t i o n do p e r m i t certain conclusions. In the three neonates (> I week old) there a p p e a r e d to be low (1314 per cent) excretion of digoxin in urine during the first 24 h after intravenous administration, a finding in good agreement w i t h previous d e m o n s t r a tions of low renal e l i m i n a t i o n of the glycoside during m a i n t e n a n c e therapy in this age-group (lisalo and Dahl, 1974; Wettrell et al., 1974). In contrast, the I month old infant e x c r e t e d 25 per cent of the intravenous dose of d i g o x i n during the first 24 h. Values in the same range have been r e p o r t e d for adult and p a e d i a t r i c patients given intravenous injections of t r i t i a t e d digoxin (Dengler, B o d e m and Wirth, 1973; Dungan et al., 1972; Hernandez et al., 1969; Marcus, K a p a d i a and Kapadia, 1964). Thus, the p r e s e n t results suggest that the b i o a v a i l a b i l i t y of d i g o x i n in solution is similar in infants and adults. Differences between infants and adults in the rate and extent of absorption cannot account for the higher doses required for therapeutic effectiveness in infants.

We are indebted to Miss Siv Karlson for skilful technical assistance and to Miss Anne Nilsson for excellent secretarial work. The investigation was supported by grants from the Swedish Medical Research Council (project no. 14X-2829).

Acknowledgements.

55

REFERENCES Andersson, K.-E., Bertler, ~., Wettrell, G.: Postmortem distribution and tissue concentration of digoxin in infants and adults. Acta paediat, scand. 64, 497-504 (1975) Bertler, ~., Redfors, A.: An improved method of estimating digoxin in human plasma. Clin. Pharmacol. Ther. 11, 665-673 (1970) Dengler, H.J., Bodem, G., Wirth, K.: Pharmacokinetic and metabolic studies with lanatoside C, e- and ~-acetyldigoxin and digoxin in man. Pharmacology and the Future of Man. Proc. 6th Int. Cong. Pharmacology. San Fransisco 1972, vol. 3, 112-126, Basel: Karger 1973 Doherty, J.E.: The clinical pharmacology of digitalis glycosides: A review. Am. J. med. Sci. 255, 383-414 (1968) Dungan, W.T., Doherty, J.E., Harvey, C., Char, F., Dalrymple, G.W.: Tritiated digoxin. XVIII: Studies in infants and children. Circulation 46, 983-988 (1972) D6hlemann, Ch., B~hlmeyer, K.: Ergebnisse vergleichender oraler und intravenSser Digitalis-Therapie bei S~uglingen. Mschr. Kinderheilk. 120, 458-461 (1972) Fleckenstein, L., Kroening, B., Weintraub, M.: Assessment of the biologic availability of digoxin in man. Clin. Pharmacol. Ther. 16, 435-443 (1974) Greenblatt, D.J., Duhme, D.W., Koch-Weser, J., Smith, T.W.: Evaluation of digoxin bioavailability in single-dose studies. New Engl. J. Med. 289, 651-654 (1973) Gutcho, S., Mc Carter, H., Rapun, R.: Radioimmunoassay of digoxin: An intercomparison of results with three methods. Clin. chem. 19, 1058-1059 (1973) Hernandez, A., Burton, R.M., Pagtakhan, R.D., Goldring, D.I.: Pharmacodynamics of 3Hdigoxin in infants. Pediatrics 44, 418-427 (1969) Horgan, E.D., Ridey, W.J.: Radioimmunoassay of plasma digoxin with use of iodinated tracer. Clin. chem. 19, 187-190 (1973) Huffman, D.H., Kauffman, R.E.: Serum levels of digoxin. J. Pediat. 82, 544-545 (1973) Huffman, D.H., Manion, C.V., Azarnoff, D.L.: Absorption of digoxin from different oral preparations in normal subjects during steady state. Clin. Pharmacol. Ther. 16, 310317 (1974) Iisalo, E., Dahl, M.: Serum levels and renal excretion of digoxin during maintenance therapy in children. Acta paediat, scand. 63, 699-704 (1974)

Jusko, W.J.: Pharmacokinetic principles in paediatric pharmacology. Pediatr. Clin. N. Amer. 19, 81-100 (1972) Krasula, R.W., Pellegrino, P.A., Hastreiter, A.R., Soyka, L.F.: Serum levels of digoxin in infants and children. J. Pediat. 81, 566569 (1972) Larese, R.J., Mirkin, B.L.: Kinetics of digoxin absorption and relation of serum levels to cardiac arrythmias in children. Clin. Pharmacol. Ther. 15, 387-396 (1974) Marcus, F.I., Kapadia, G.J., Kapadia, G.G.: The metabolism of digoxin in normal subjects. J. Pharmacol. exp. Ther. 145, 203-209 (1964) Neill, Catherine, A.: The use of digitalis in infants and children. Progr. cardiovasc. Dis. 7, 399-416 (1965) Nyberg, L., Andersson, K.-E., Bertler, ~.: Bioavailability of digoxin from tablets. 3. Availability of digoxin in man from preparations with different dissolution rate. Acta pharm, suecica 11, 471-492 (1974) Oliver, C.G., Taxman, R., Frederickson, R.: Influence of congestive heart failure on digoxin blood levels. Symposi[~n on digitalis, Oslo, Norway. Ed. by O. Storstein. S. Nittergauge, L. Storstein, p. 336-347, Oslo, Norway: Gyldendal Norsk Forlag 1973 Redfors, A.: Plasma digoxin concentration its relation to digoxin dosage and clinical effects in patients with atrial fibrillation. Brit. Heart J. 4, 383-391 (1972) Rutkowski, Monika M., Cohen, S.N., Doyle, E.F.: Drug therapy of heart disease in pediatric patients. Part II. Amer. Heart J. 86, 270275 (1973) Sanchez, N., Sheiner, L.B., Halkin, H., Melmon, K.L.: Pharmacokinetics of digoxin: Interpreting bioavailability. Brit. med. J. 1973 IV, 132-134 Wagner, J.F., Christensen, M., Sakmar, E., Blair, D., Yates, J.D., Willis III, P.W., Sedman, A.J., Stoll, R.G.: Equivalence lack in digoxin plasma levels. J. Amer. med. Ass. 224, 199-204 (1973) Wettrell, G., Andersson, K.-E., Bertler, ~., Lundstr6m, N.R.: Concentrations of digoxin in plasma and urine in neonates, infants, and children with heart disease. Acta paediat. scand. 63, 705-710 (1.974) G. Wettrell, M.D. Dept. of Paediatrics University Hospital S-221 85 Lund Sweden

Absorption of digoxin in infants.

The bioavailability of digoxin in solution was studied in 4 newbron infants with heart failure. Serum digoxin concentrations were determined by radioi...
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