Digoxin Metabolism in Obesity
By GORDON A. Ewy, M,D., BERTRON M. GROVES, M.D., MICHAEL F. BALL, M.D.,
LANA NIMMO, BARBARA JACKSON, ANl,D FRANK MACUS, M.D.
SUMMARY
A single intravenous dose of tritiated digoxin was given to five obese patients
before and after a mean loss of 102 pounds in weight. There were no significant
differences in the blood concentrations of digoxin before and after the weight reduction.
Likewise, there were no significant differences in the blood concentrations of digoxin
when these data were corrected for fat-free body weight.
These findings are consistent with the thesis that fat-free body weight is a more
important determinant of the blood concentration of digoxin than total body weight is.
The clinical implication of this study is that digoxin dosage may be erroneously high
if calculated on the basis of total body weight for obese individuals.
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Additional Indexing Words:
Total body weight
Fat-free body weight
Tritiated digoxin
in the dog.4 These findings suggest that lean
body weight or fat-free body weight might be
more important than total body weight in determining the blood concentration of digoxin.
The present study was designed to investigate further the influence of body weight on
the blood concentration of digoxin in humans.
To obviate the problem of subtle differences
of digoxin metabolism among subjects, each
obese subject was used as his own control and
was studied before and after weight reduc-
DIGOXIN has generally been prescribed
in the adult without consideration of
body size or weight.' However, Ewy and
associates2 found a higher concentration of
digoxin in the blood of elderly individuals of
smaller body weight than in younger, heavier
subjects, after a single intravenous dose of
tritiated digoxin. The blood concentrations of
digoxin of the two groups were not different
when the data were corrected for body
weight. It was, therefore, concluded that body
weight is an important determinant of blood
concentrations of digoxin. Jelliffe3 has likewise
stressed the importance of body weight in
determining digoxin dosage.
Very low concentrations of tritiated digoxin
have been found in the adipose tissue in man
(JE Doherty: Unpublished observations) and
tion.
Methods
Five obese subjects, ages 19 to 27 years, were
hospitalized in the Clinical Study Unit of the
Georgetown University Hospital for studies of
change in body composition during dietary
weight reduction under the supervision of one of
the authors (M.B.).5
Informed consent was obtained from all
subjects prior to the initiation of the study. Each
From the Department of Internal Medicine,
University of Arizona College of Medicine, Tucson,
Arizona, and the Department of Medicine, Georgetown University School of Medicine, Washington,
D. C.
Address for reprints: Dr. Gordon A. Ewy,
Department of Internal Medicine, University of
Arizona College of Medicine, Tucson, Arizona
85721.
Received April 2, 1971; revision accepted for
publication July 20, 1971.
subject's medical history was elicited, and
physical examination was performed on admission
to the hospital. Laboratory data obtained on
admission included chest roentgenogram, electrocardiogram, hemogram, urinalysis, determination
of blood urea nitrogen, serum creatinine, electrolytes, calcium, phosphorus, and glucose. The
history, physical examination, and laboratory tests
did not reveal any abnormalities except obesity.
Laboratory studies performed periodically included serum electrolytes, blood urea nitrogen, and
810
Clrculation, Volume XLlV, November 1971
DIGOXIN METABOLISM
811
were calculated for each subject
between the second and fourth day after digoxin
was injected.
The concentration of digoxin was measured
by
methods previously reported from this
laboratory.6 Briefly, the blood samples were
extracted with 20% ethanol and chloroform. The
solvent was evaporated and an aliquot was
transferred to a counting solution. The recovery of
radioactivity when tritiated digoxin was added to
blood prior to extraction was 98.6 4.5%
(mean + 1 standard deviation). Radioactivity of
each specimen was counted on a model 314 EX
Packard tricarb liquid scintillation counter. The
counts were corrected for quenching by adding
tritiated toluene of known activity and recounting. Differences in radioactivity between the two
groups were analyzed using the two-tailed
Student t-test.7 The rate of decrease in the
concentration of digoxin before and after weight
reduction was analyzed for possible significant
differences by homogeneity of regression.8
cr-eatininie. Mleasuremenits of total body
wveight anid fat-free bodv weiglht were made on
creatinine
seruim
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admllissioni, ser ially thlroughout the period of
weighlt loss, and prior to discharge on each
stubject bv methods previously described.5 All
suibjects remaiined on the metabolic unit for 7 to
129 miionths durinig wvhich time they were given a
lowx-calorie, liquid formula diet. Digoxin metabolism was sttudied at least twice in each subject,
once at the beginning and once at the end of
weight rieduction. An intermediate study was
doine in thlee of the five subjects.
The digoxiin study was conducted as follows: a
single, intravenous injection of 0.5 mg of tritiated
digoxin* (specific activity, 144 uc/ml) as a 5%
alcoholic solution in saline was given over a
period of 1 minute. Zero time was taken as the
end of the injection. Specimens of venous blood
were obtaiined from the opposite antecubital vein
15, 30, anid 60 minutes and 2, 4, 6, 8, and 12
houirs after the injection and daily thereafter for 5
davs. The 24-hour endogenous clearances of
Results
*Tritiated digoxin
Bulrr otighs
York.
was most kindly supplied by the
Wellcome Company, Tuckahoe, New
The age, sex, total and fat-free weights
before and after weight reduction, and weight
Table 1
Age, Sex, and Total Fat-Free Weight before and after Reduction of Weight
Subject
Age (yr)
Sex
D.C.
G.F.
J.B.
J.J.
F.F.
Average
2.5
19
20
27
20
22
F
F
F
F
M
Height
(in)
Initial
260
246
262
211
4 05
277
62
68
70
61
71
66
Weight (1b)
Fat-free body weight (fb)
Final
Loss
Initial
Final
Loss
Total fat
loss (1b)
1.52
178
172
147
108
68
90
64
132
141
124
108
185
138
112
123
108
101
139
116
20
18
16
7
46
22
88
50
74
57
13,5
80
224
181
175
102
Table 2
Blood Concentrations of Digoxin in Nanograms per Milliliter of Blood
D.C.
12 hr
1 day
2 day
3 day
4 day
5 day
G.F.
Before
After
0.547
0.388
0.323
0.245
0.177
0.099
0.707
0.572
0.417
0.282
0.190
0.136
J.B.
F.F.
J.J.
Before
After
Before
After
Before
After
Before
After
0.804
0.676
0.502
0.378
0.282
0.225
0.824
0.864
0.624
1.070
0.570
0.370
0.320
0.749
0.800
0.321
0.284
0.356
0.187
0.600
0.683
0.387
0.293
0.431
0.350
0.249
0.186
0.174
0.218
0.123
0.770
0.6.55
0.340
0.300
0.430
0.290
0.210
0.150
0.321
0.28,5
0.223
0.195
0.54.5
0.386
0.314
0.220
0.1.50
t-test for paired data
Hours 0-4
P
Days 1-5
P
>0.050
>0.050
>0.0150
<0.010
>0.025
>0.100
>0.050
>0.100
>0.200
<0.025
Circulation, Volume XLIV, November 1971
EWY ET AL.
812
- Initial Study
Final Study
5. Mean 1 SD
10
A-
5.0
NANOGRAMS
DIGOXIN /ML--BLOOD
1.0
0.5 _4i*...
00
0.10
2
4
6
HOURS
B
10
12
i
t
2
3
4
5
DAYS
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Figure 1
Meani concentration of digoxin ini blood at intervals
followiing a single intravenous inijection of 0.5 mg of
tritiated digoxin given to each of five obese subjects
before (initial) and after (final) a mean individual loss
of 102 pounds. Note that the digoxin concentrations
are plotted on the ordinate in a semilogarithmic manner. There is no significant difference in the blood
concentrations before and after loss of weight.
losses are listed in table 1. The average age of
five subjects was 22 years; average duration of
hospitalization was 9 months; and the average
loss of weight was 102 pounds, of which 22
pounds was loss of fat-free body weight.
There was no significant difference in the
creatinine clearance before and after weight
loss ( 126 ± 10 versus 122 + 7 ml/ min).
Blood concentrations of digoxin and metabolites* before and after weight reduction were
not significantly different after a single intravenous dose of tritiated digoxin (table 2; fig.
1). The blood digoxin half-life, calculated
from 24 hours to the fifth day, was 58 hours
before and 60 hours after weight loss. This
difference was not significant. There was
likewise no significant difference in the urinary
excretion of digoxin before and after weight
loss.
The lack of difference in the blood concen*Hereafter, digoxin will refer to digoxin and
metabolites. The concentration of digoxin in the blood
is usually too small for satisfactory fractionation.
However, extraction and partition chromatography of
urine in patients previously studied indicates that
nearly 90% of the radioactivity migrates with
unchanged digoxin and the remainder with the cardioactive mletabolites digoxigenin monodigitoxosiide and
digoxigenin bisdigitoxoside.9 Studies of the metabolism of tritiated digoxin in renal insufficiency in dogs
and man indicate that the drug is likewise excreted
primarily unchanged.10
tration of digoxin before and after weight
reduction is best illustrated in patient F. F.
(fig. 2), who lost the most weight-a total of
181 pounds. To determine whether the
digoxin concentrations were related to fat-free
body weight, the blood concentration of
digoxin before and after weight reduction was
calculated in terms of fat-free body weight.
Again no significant differences were found.
Discussion
We could not identify total body weight as
a determinant of blood concentration of
tritiated digoxin in these studies of obese
subjects. As previously mentioned, our studies
of digoxin metabolism in the elderly suggested
that body weight is a determinant of blood
concentration of digoxin.' In our earlier
studies, the intravenous administration of
tritiated digoxin resulted in blood concentrations during the first day that were higher in a
group of elderly men (average weight,
143 + 25 pounds) as compared to the younger, heavier volunteers (average weight,
173 + 29 pounds). Although the creatinine
and digoxin clearances were lower in the
elderly men, these factors could not account
for the higher blood concentrations of digoxin
throughout the first day of the study. When
the blood concentrations of digoxin were
corrected for body weight, this difference was
PATIENT F.F.
-_
*--
.. 405 Ibs.
255 lbs.
A224 Ibs
5.0
NANOGRAMS
DIGOXIN /ML
BLOOD 1 0
4
0.5
0.1
I
2
4
I/
.
I
8
6
HOURS
10
12
1
2
3
DAYS
4
5
Figure 2
Concenitration of digoxin in blood at intervals following a single intravenous dose of 0.5 mg of tritiated
digoxin in patient F. F. before loss of weight and
after losses of 150-181 pounds. Note that the digoxin
concentrations are plotted on the ordinate in a semilogarithmic manner. In spite of these large reductions
in total body weight, there are no differences in the
blood concentrations of digoxin.
Circalation, Volume XLIV, November 1971
DICOXIN METABOLISM
813
Wt. 277 lbs.
DIGOXIN
BEFORE
WEIGHT
REDUCTION
FAT FREE
**@*'3
. .
b.
. . ..lb
.
FAT
*
VA.. .
%///////////////
AF TER
WEIGH T
REDUCTION
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Mean body composition of five obese subjects before
and after weight reduction. The mean loss of total
body weight was 102 pounds, of fat-free body weight
22 pounds, and the mean loss of fat was 80 pounds.
In spite of the large differences in total body weight,
fat-free body weight and blood digoxin concentrations
were little changed.
longer significant. These observations were
interpreted as indicating that body weight was
a determinant of the blood concentrations of
digoxin. Additional support for this conclusion
was the observation that the one elderly
patient (J.R.) whose body weight (182
pounds) was greater than the mean weight
of the other elderly patients and closer to that
of the younger, heavier volunteers had blood
concentrations of digoxin that were similar to
the younger volunteers.'
Jelliffe3 has likewise stressed the importance
of body weight in determining digoxin dosage.
He and his associates have developed computer programs and a nomogram from which the
daily maintenance dose of digoxin is calculated using the desired blood concentration,
renal function, and total body weight.
The observation by Harrison and associates4
and Doherty ( [JE] Unpublished observations) that the concentration of digoxin in
skeletal muscle of man and the dog is many
times higher than in fat, prompted the present
study. Our findings are shown diagrammatically in figure 3. Before weight reduction, the
average total body weight was 277 pounds,
and the average fat-free body mass was 138
pounds. Following a mean loss of 102 pounds,
there was a gross reduction in body fat but
only a small reduction in fat-free body weight.
no
Circulation, Volume XLIV, November 1971
The blood concentration of intravenously
administered digoxin was similar before and
after weight reduction.
The problem of the interrelationship of
body weight and blood concentration of
digoxin may be clarified by the hypothesis
that the concentration of digoxin in blood
varies inversely with fat-free body weight, but
is little affected by marked alterations in body
weight due to adipose tissue. This hypothesis
is consistent with the data from the present
study as well as the study of digoxin
metabolism in the elderly. Although fat-free
body weight was not determined in the study
of digoxin metabolism in the elderly, the
younger individuals were muscular and therefore probably had a larger, fat-free body
weight than the elderly subjects.
The clinical implications of this study are
that digoxin dosage may be erroneously high
if calculated on the basis of total body weight
in obese individuals. If the individual is a
large, muscular man who would be expected
to have a large, fat-free body mass, then a
dose of digoxin larger than normal may be
needed to achieve a blood concentration equal
to that given to a smaller, less well-muscled
individual. However, if the patient is obese,
the dose of digoxin required to achieve a
certain blood concentration should be no
greater than in the less obese or thin subject of
comparable height who may have an equal
fat-free body mass.
The findings of this study may not be
applicable to cardiac glycosides such as
digitoxin that are less polar or more fat soluble
than digoxin. Should digitoxin be found in
appreciable concentrations in adipose tissue,
then the obese patient might be expected to
require more digitoxin than the less obese
individual to achieve similar concentrations of
the drug in blood and heart.
Acknowledgment
We are indebted to Dr. Oscar Thorup, Jr. for his
critical review of this manuscript; to Dr. Stanley
Bloomfield of Burroughs Wellcome and Company,
Tuckahoe, New York, for his assistance; to the
Medical Illustration Department of the Tucson
Veterans Administration Hospital, Tucson, Arizona,
for the medical illustrations; and to Mrs. Mildred
EWY ET AL.
814
Thielen and Mrs. Betty Bacon for secretarial
assistance.
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Circulation, Volume XLIV, November 1971
Digoxin Metabolism in Obesity
GORDON A. EWY, BERTRON M. GROVES, MICHAEL F. BALL, LANA
NIMMO, BARBARA JACKSON and FRANK MARCUS
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Circulation. 1971;44:810-814
doi: 10.1161/01.CIR.44.5.810
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