Pharmacokinetics and Bioavailability of Digoxin Capsules,

Solution and Tablets After Single and Multiple Doses

BRIAN L. LLOYD, MB, MRACP The bioavailability of single doses of dtgoxln capsules (0.4 mg), dlgoxin
DAVID J. GREENBLATT, MD sokrtlon (0.4 mg) and reference tabtets (0.5 mg) was compared wtth that
MARCIA D. ALLEN, RN of single intravenous doses (0.4 mg) of digoxin using measurement of 24
JEROLD S. HARMATZ hour urinary excretion and area under the plasma concentration curve.
THOMAS W. SMITH, MD, FACC
The absolute systemic availabtltty of all three oral preparations was sig-
Boston, Massachusetts ntficantly less than 100 percent. The bioavallabtltty of capsules and so-
lution was nearly ldentlcal(79 percent and 76 percent, respectively, as
assessed with values for area under the concentration curve and 65
percent and 62 percent as m with urtnary excretion values); both
forms had greater systemic avallabtltty than the tablet, which had bio-
availabt5ty vakres of 50 percent ustng area under the curve and 41 percent
using urinary excretion. Capsules and solution also were similar In peak
plasma dtgoxin levels achieved (3.7 and 3.1 ng/ml), time of peak con-
centratlon (0.8 and 0.6 hour after dosage) and apparent first order ab-
sorption half-life (11.3 and 10.2 minutes); both capsules and solutlon
differed stgntflcantly from tablets (peak level 1.6 ng/ml, time of peak
concenkatkx~ 1.2 hours and absorptkn half-5fe 27.1 mtnutes). Single dose
findlngs were substantiated when steady state plasma levels and 24 hour
urinary excretion values were measured from days 11 through 16 of the
period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and url-
nary excretion values (45.1 percent of dose) for capsules were nearly
identical to those for solution (0.6s ng/ml and 42.5 percent of the dose),
and values for both capsules and solution were signlftcantly greater than
those for tablets. Withtn- and between-subject variation in bioavailablllty
was similar for the three oral preparations. Thus the single dose bio-
availability study was predictive of the steady state findings. The bto-
availability of digoxin capsules is equivalent to that of a solution and
significantly greater than that of a reference tablet formulation.

From the Clinical PharmacologyUnit, fdassa-

dwsettsQeneralHcepttal;andthecerdiovascular
Dlvlsion, Deparhwnt of Medicine, Peter Sent
Brigham Hospital, Boston, Massachusetts. This
study was supported in pert by a grant from
Anlw-staw kborawm, MouIt Pmspect, lllinols
and by @ants l-H.-18003 (to Dr. Smith) and MK
12279 (to Dr. Qreenblatt and Mr. Harmatz) from
the fMofnil Institutt3s of Heafth, Betfwsda,
Mwyland.Dr.Lbydwasa Resew& Fellow of ths
N&bd IWrt Found&n of Austmfla. Manuswipt
rece&ed Novembw 30,1977; revised manuscript
received January 30,1978. accepted February 1,
1978.
Address for reprints: David J. Greenblatt. MD,
Clinical Pharmacology Unit, Massachusetts
General Hospital, Boston, Massachusetts
02114.
Achievement of stable and predictable plasma digoxin concentrations
during long-term digoxin therapy remains difficult because all currently
available oral digoxin preparations are incompletely and variably ab-
sorbed from the gastrointestinal tract.’ An optimal fixed dose oral di-
goxin preparation would have a predictable high level of bioavailability
with minimal variation in the extent of absorption within and between
subjects. Gelatin capsules containing digoxin in solution reportedly have
improved bioavailability and may be a potential replacement for digoxin
tablets.28 However, the extent of improved bioavailability of capsules
and the issue of whether steady state plasma digoxin levels are less
variable than with existing standard preparations have not been settled
by previous studies. We investigated the extent and variability of digoxin
absorption from the capsule preparation after single and multiple doses
in comparison with those of standard reference tablets and solution.

July 1978 The Amerfcan Journal of CARDfOLOGV Volume 42 129

PHARMACDKINETICS AND BIOAVAILABILITY OF DIGDXIN-LLOYD ET AL.

Methods Solution: 0.4 mg reference standard digoxin dissolved in

Subjects: Twelve healthy male volunteers (Table I) served
as experimental subjects after giving informed consent. None
had any demonstrable medical disease.
Procedure: Each subject received the following four di-
goxin preparations in random sequence:
2 ml of U.S.P. ethanol and 198 ml of water. The container was
rinsed with 40 ml of water, which was also ingested.
Tablets: Two 0.25 mg tablets of reference standard digoxin
(Lanoxine, Burroughs Wellcome Co., lot no. 022-1, with an in
vitro dissolution rate of 75 percent in 1 hour).

TABLE I
Pharmacokinetic Variables After Intravenous Adminlstratlon of Digoxln

Case Age Weight f112a t112r Clearance

no. (yr) (kg) (hr) (hr) t&w (IitezIkg) (Ilte%kg) (ml/kg per min)
1 33 80.0 l l l . l l

80.9 0.05 0.42 83.01 0.128 10.95 2.01

3 34
81.8
84.5
0.19
0.44
1.02 37.88
10.03
0.252
0.308
8.43
4.08
2.59
4.88
: 25 79.5 0.32 10.19 0.501 8.77 7.78
8 28 82.7 0.15 0.85 48.21 0.309 14.50 3.83
29 85.9 0.39 11.07 0.577 7.83 8.17
3 27 72.7
88.2
0.41
0.43
27.70
18.34
0.821
0.534
8.79
8.87
3.88
4.85
1;
11
St!
27
88.2
77.3
0.24
0.08 0.88
9.70
27.73
0.315
0.179
3.15
8.75
3.74
3.85
12 29 81.8 0.08 0.82 48.21 0.188 12.43 3.11
Mean 27.9 77.0 0.24 0.71 27.82 0.35 8.41 4.35
SE fl.O f1.9 f0.04 fO.10 f5.54 f0.053 fl.O1 f0.59
Comoosite 77.0 0.14 0.81 19.3 0.28 8.72 4.47

lktdicates that least-squares analysis could not be performed because of outlying data points.
SE = star&d error; tuza = distributionhalf-life; tllh = intermediate half-life; tl12@= elimination half-life: Vd = total apparent volume of distribution;
VI = volume of central compartment.

INTRAVENOUS (0.4 mg)

CAPSULE (0.4 mg)

c
0.0 4.0 8.0 12.0 16.0 20.0 24.0

SOLUTION (0.4 mg)

FIGURE 1. Plasma digoxln wn-
TABLETS (0.5 mg) centrations after admintstratfon of
ask@edoeeofintreMwwKgdlgoxin
and of the three oral dlgoxtn prep
aratkxls. Each point Is the meen for
all 12 subjects at the time shown
(standard errors, omitted fcf clarity,
will be provided by the author on
request). Also shown are the phsr-
0.0 4.0 8.0 12.0 18.0 20.0 24.0 macokinetlc functions determined
from least-squares regression
HOURS analysis (see text).

130 July 1978 The American Journal d CARDIDLDGY Volume 42

 !WARMACOKINfiTICS AND BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.

TABLE II
Pharmacoklnetlcs d Dlgoxin Absorption From the Three Oral Preparations
Capsule(0.4
mg) Solution (0.4 mg) Tablet (0.5 mg)
Peak Peak Peak
Time Time Time
Peak (hr Lag Peak (hr Lag Peak (hr Lag
Case Level after Time f112a Level after Time ha Level after Time f112a
no. @g/ml) dose) (min) (min) @g/ml) dose) (min) (min) (ng/ml) dose) (min) (min)
3.5 1.0 l l 3.3 0.75 11.8 11.0 2.1 0.75 14.4 4.2
3.5 1.0 + l t.: 0.5 11.5 7.2 0.8 1.5 15.0 74.3
::: 0.75 28.2
l l 2:8 0.5 10.7 11.2l 0.9
1.2 2.0
1.0 13.8
l 31.3
l

z.: 0.75 14.4

15.0 2G
19:o ;:: ::;5 1;2
10:8 34.3
9.8 1.0
1.8 0.75
1.5 17.4
14.4 36.8
17.6
2:8 0.5 15.0 3.5 13.7 1.0 1.7 1.0 11.4 7.0
S:; 0.75
1.0 1;o lIj9 42:: 00:;5
0.5 12.6 8.5
8.1 2.9
1.3 2.0
1.5 12.0
l 35.6
l

2.9 0.75 29:8 0:9 X:: 0.75 184:: 13.1 2.0 1.0 13.8 31.5
4.2 0.75 12.6 7.8 f.8 0.5 9.8 6.1 1.6 0.5 15.0 0.7

f :; 0.75
0.8 18.1
15.0 12.4
11.3 311 X:: 11.9
12.5 10.2
4.2 1.6
1.5 1.0
1.2 13.9
11.4 32.0
27.1
*SE f0.3 f0.04 f2.4 f3.1 f0.3 f0.04 f0.8 f2.6 f0.2 fO.l ho.6 f6.8
Comwsite 3.4 0.75 15.0 19.8 2.9 0.5 11.4 7.4 1.2 1.0 12.4 22.0

l Indicates that least-squares analysis could not be performed because of outlying data points.

Capsules: Two 0.2 mg capsules of digoxin prepared in a
liquid-filled soft gelatin capsule (Arnar-Stone Laboratories,
lot. no. 746P).
Intravenous preparation: 0.4mg of digoxin injection (La-
noxina, lot no. 994-S) diluted with 46.4 ml of sterile 5 percent
dextrose in water and infused into an antecubital vein by a
constant rate infusion pump over 1 hour.
Tablet and capsule preparations were ingested with 240 ml
of water. Subjects fasted overnight before each oral dosage
trial and abstained from further food or liquid for 4 hours after
drug administration. Venous blood samples were drawn
through an indwelling catheter, or by venipuncture, before
dosage and 0.25,0.5,0.75,1.0,1.5,2.0,2.5,3,4,6,8,12 and 24
hours after digoxin ingestion or the start of infusion. Addi-
tional samples were drawn at 65 and 75 minutes after the start
of intravenous infusion. A 24 hour urine collection was begun
at the time of digoxin administration.
After the initial 24 hours of study, each oral preparation
was taken daily at 9 AM for 14 additional days. “Steady state”
blood samples were collected just before the daily dose on days
11 through 16.Urine was collected in 24 hour periods after
doses 11,12,13,14 and 15. After the final dose of each oral
preparation, 24 hours of blood sampling was performed as in
the case of the initial dose. Subjects remained ambulatory
during testing, and at least 14 days elapsed between each trial
to permit complete excretion of digoxin from the preceding
period.
Analysis of plasma and urine: Plasma and urine samples
were stored at -20’ C until the time of assay. Digoxin con-
centrations in plasma and urine were determined with ra-
dioimmunoassay as previously described.gJo
Analysis of data: Plasma digoxin concentrations after in-
travenous infusion were analyzed with the computer using
iterative nonlinear least-squares regression techniques,11J2
as described in detail elsewhere.13 Data points for individual
subjects, as well as for composite points calculated as the
across-subject mean plasma concentrations at corresponding
points in time, were fitted to bi- or triexponential functions
consistent with two- or three-compartment pharmacokinetic
models. The functions of best fit were then used to calculate
the following pharmacokinetic variable@-is: distribution
half-life (ti/sJ, intermediate pi half-life (ti/s,) when appro-
priate, elimination half-life (ti/sg), volume of the central
compartment (Vi), total apparent volume of distribution
using the area method (V,) and total clearance.
After oral administration of digoxin, individual and com-
posite data points were similarly analyzed and fitted to the
sum of the smallest number of exponential terms necessary
to describe the data adequately. Fitted functions were used
to calculate the lag time (tc) elapsing before the start of first
order absorption, and the apparent first order absorption
half-life (tijs,). In all cases iterative analysis proceeded until
the convergence criteria were met or 50 iterative steps were
completed.
Plasma digoxin concentrations for the 24 hours after the
first and last dose of each preparation were used to calculate
the area under the 24 hour plasma concentration curve using
the trapezoidal method. Single dose bioavailability was as-
sessed by comparing the area under the plasma concentration
curve and the 24 hour urinary excretion values after each
preparation, using repeated-measures analyses of variance
and the Newman-Keuls test of paired comparisons.17 Relative
bioavailabiity of the three oral preparations during long-term
therapy was similarly assessed from steady state plasma
concentrations and urinary excretion values. Appropriate
adjustments were made for differences in oral doses of tablets,
capsules and solution.
Between- and within-subject variations in the various
measures of bioavailability were expressed as coefficients of
variation. The between-subject coefficient of variation for a
given mode of treatment was determined as the standard
deviation for that treatment divided by the treatment mean,
expressed in percent. When multiple measurements were
made for the same subjects within a given treatment, an
overall within-subject coefficient of variation for that treat-
ment was calculated by weighted pooling of each individual
subject’s coefficient of variation.18
Results
Single dose pharmacokinetics: Figure 1 shows
single dose composite data points for all four modes of
digoxin administration, together with functions of best
fit.

July 1978 The American Journal of CARDfOLOGY Volume 42 131

PHARMACOKINETICS AND BIOAVAILABILITY OF DIGDXIN-LLOYD ET AL.

Disappearance of digoxin from plasma after intravenous
infusion was best fitted by two exponential phases in six
subjects and by three exponential phases in five subjects
(Table I). In the remaining subject (Case l), a satisfactory fit
could not be achieved because of outlying data points. The
mean apparent elimination half-life was 27.8 hours, the total
volume of distribution 8.4 liters/kg and the total clearance 4.35
ml/min per kg. These values are consistent with data in other
reports of intravenous digoxin pharmacokinetics in normal
subjects.lg
Peak serum digoxin concentrations (in ng/ml) averaged
3.7 after capsule administration, 3.1 after solution, and 1.6
after tablets (Table II). Analyses of variance indicated that
the overall difference among preparations was significant (F
= 46.5, d.f. = 2,22, P <O.OOl). The difference between capsule
and solution also was significant (P KO.05). The peak level was
attained an average of 0.8 hour after dosing with capsules, 0.6
hour with the solution, and 1.2 hours with tablets. Again the
overall difference was significant (F = 11.9, d.f. = 2,22, P
6.0, i

25.0 -

. ~- . =WRLNENO”S
.~
(0.4 mg)
.o 0 CAPSULE (0.4 mg)

20.0 -

n* 0

. x

15.0 -
-+- -4
LG.0
. . ”

IO.0 -
.
.
----F--- ---w---
00
x
INTRAVENOUS O.
xx
CAPSULE
SOLUTION
5.0 -

ii - l = lNTRNEHOUS (0.4 ms)

x = SOL”TlOH (0.4 mg)
TABLETS
0.0 -1

40.0 -

50.0 - _________.
x
0.0 2.0 4.0 6.0 8.0 li.0 iii.0
0
. 0
xx 6.0
. 0

INTRAVE&JS __________ x
-___---- ----*----
20.0 - #-- x
x
00
00 x i
CAPSULE ’ __a!iA~__

.3
- . = ,HTRAvEHO”S (0.4 mg)
- - mg)
x h
12 TABLETS (0.5

10.0 -

TAB&S
SOL:TlON
.
0.0 -1

FIGURE 2. Area under the 24 hour plasma concentration cuve (above) 1.0 2.0 4.0 6.0 8.0 7s A.0
and 24 hov urinary excretion rate of digoxin (below) after a single dose HOURS
of intravenous dlgoxin and of the three oral digoxin preparations. Indi-
vidual values and means (* standard error) for all subjects are shown. FKiURE 3. Single dose plasma concentration curves for intravenous
Values for area under the 24 hour plasma concentration curve after digoxin in comparison with curves for each of the three oral prepara-
administration of tablets (above) were corrected for the difference in tions. Each point is the mean (rt standard error) for all 12 subjects at
dose. the time shown.

132 July 1979 The Am&can Journal of CARDIOLDGY Volume 42

 PWARMACOKlNETlCS AND BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.

<O.Ol). The tablet-capsule and tablet-solution differences sorption half-life also were significant (F = 4.24, d.f. = 2,26,
were significant (P <O.Ol), whereas solution and capsules were P <0.05); values of tl/a for capsules and solution were similar
not significantly different. (11.3 and 10.2 minutes, respectively), and values for both were
Pharmacokinetic functions were determined in 8 subjects smaller than that for tablets (27.1 minutes).
after ingestion of capsules, 11 subjects after solution and 10 The findings strongly suggest that the rate of digoxin ab-
subjects after tablets. One-way analysis of variance indicated sorption from capsules and solution is very similar. However,
an overall difference in apparent lag time before the start of digoxin is more slowly absorbed from tablets; peak levels are
absorption (F = 5.95, d.f. = 2,26, P <O.Ol) although differences reached later after dosing, and absorption half-life values are
between the preparations were small and not likely to be of longer. For all three preparations there was a lag time between
substantial clinical importance (Table II). Differences in ab- administration and the start of absorption.
Single dose bioavailability: Analysis of variance indicated
a significant difference among preparations in dose-adjusted
values of the 24-hour area under the concentration curve (F
= 10.25, d.f. = 3,33, P <O.Ol). Systemic availability of all three
oral preparations, as judged by comparison of the area under
the concentration curve and the intravenous value, was sig-
nificantly less than 100 percent. Mean 24 hour area under the
concentration curve for capsules was 79.2 percent of the in-
travenous value (P <0.05, Newman-Keuls test); the solution
x averaged 76.2 percent of the intravenous value (P <0.05), and
0
dose-corrected tablets averaged only 49.5 percent of the in-
:: travenous value (P <0.05) (Fig. 2). Figure 3 shows the com-
posite intravenous curve compared with that of each of the
x
oral preparations.
Twenty-four-hour urinary excretion of digoxin after single
doses yielded similar findings. The overall difference between
the four treatments in 24 hour urinary excretion was highly
08 significant (F = 36.06, d.f. = 3,33, P <O.OOl). An average of 130
0 xx mg of digoxin (32.5 percent of the dose) was excreted during
CAPSULE
x
24 hours after intravenous dosage. Excretion after adminis-
(0.4 ms) SOLUTION
A
tration of capsules averaged 62.5 percent of the intravenous
(0.4 ms) TABLETS value (P CO.01); for solution, excretion was 61.8 percent of the
(0.5 m9) intravenous value (P <O.Ol). Digoxin excretion after ingestion
of tablets, when corrected for dose, averaged only 40.9 percent
of the intravenous value (P <O.Ol) (Fig. 2).
The findings indicate that the systemic availability
of all oral digoxin preparations was significantly less
than 100 percent. The bioavailability of capsules was
x approximately equivalent to that of the solution,
whereas that of the tablet preparation used in this study
x
x

_____*_____

08
0 x
0 xx TABLE III
CAPSULE x
Comparison of Wlthln- and Between-Subject Variability In
Bloavailabillty*
SOLUTION
Mode of Administration
intravenous Capsule Solutlon Tablets
Single dose AUC 28.4 25.9 26.9 45.1
(between subjects)
Single dose UE 16.0 18.6 33.6 22.7
TABLETS (between subjects)
Steady state AUC 28.9 24.8 30.2
(between subjects) ’
Steady state plasma level . . 18.7 22.5 20.5
(pooled within subjects)
Steady state plasma level . 22.6 31.6 26.3
(between subjects)
FIGURE 4. Steady state plasma concentrations (above) and 24 hour Steady state UE 21.6 23.3 19.9
urinary excretion rates (below) for the three oral preparations during (pooled within subjects) .
multiple dose therapy. Each data point is the mean of four to six daily Steady state UE 14.6 17.1 24.5
rneas~ements for a given s&ject. The figure shows the across-subject (between subjects)
mean (& standard error) of these individual mean values. The urinary Expressed as coefficient of variation (in percent).
l

excretion data are expressed as percent of dose, thereby taking into AUC = area under the plasma concentration curve; UE = urinary
account differences in dosages among the preparations. excretion.

July 1978 The American Journal of CARDIOLOGY Volume 42 133

PHARMACOKINETICS AN0 BIOAVAIIABILITY OF DIGOXIN-LLOYD ET AL.

o.o*
0.0 2.0 4.0 0.0 0.0
I;.0 1
21.0

HOURS

0 x -----a----
0 A
SOLUTION
CAPSULE

FIGURE 5. Above, plasma digoxin concentration during

TABLETS
the final steady state dosage interval. Each point is the
(DOSE-CO~G~ECTED)
mean for all subjects at the times shown. Below, area
under the 24 hour plasma concentration curve during the
final dosags interval at steady state. Individual values and
mean (k standard error) for all 12 subjects are shown.

was substantially less than that of either the solution
or capsules.
Steady-state bioavailability: Mean steady state serum
digosin concentrations (in ng/ml) based upon four to six
measurements in each subject in each treatment condition
were: 0.70 for capsules, 0.69 for solution and 0.69 for tablets
(Fig. 4). After correction for dose, the overall difference among
treatments was significant (F = 10.04, d.f. = 2,22, P <O.Ol).
The tablet-solution and tablet-capsule differences were highly
significant (P <O.Ol for both comparisons), whereas values
for capsules and solution were essentially identical. Likewise,
24 hour urinary excretion in the steady state varied signifi-
cantly among treatments (F = 8.40, d.f. = 2,22, P CO.01).
Mean values (for percent of the dose) were: 45.1 for capsules,
42.5 for solution and 35.0 for tablets (Fig. 4). Again the cap-
sule-tablet and solution-tablet comparisons yielded highly
significant differences (P <O.Ol), whereasthe capsule-solution
comparison showed no significant difference.
Figure 5 shows the composite serum concentration curves
for all three oral preparations during the steady state dosage
interval. The area under the 24 hour concentration curve at
steady state, after correction for dose, differed significantly
among preparations(F = 24.75,d.f. = 2,22,P <O.Ol).The area
under the concentration curve values for capsules and solution
was not significantly different, whereas the area for tablets
was significantly less than that for capsules and solution (P
CO.01) (Fig. 5).
Thus the single dose findings were supported by the
multiple dose study, demonstrating that capsules and
solution had essentially identical bioavailability, which
was superior to that of the standard tablet preparation
under study.
Between- and within-subject coefficients of
variation: Table III summarizes the coefficients of
variation for all modes of treatment. For the two single

134 July 1979 The American Journal of CARDIOLOGY Volume 42

 PHARMACDKINETICS AND BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.
dose measures of bioavailability, intravenous digoxin
and oral capsules had approximately equal coefficients
of variation, which were less than or equal to those of the
solution and tablet preparations. For steady state
plasma levels and urinary excretion of digoxin, within-
and between-subject coefficients of variation for cap-
sules also were less than or equivalent to those of solu-
tion and tablets. For all three treatments, between-
subject coefficient of variation values for steady state
plasma levels were higher than within-subject values.
This was also the case for steady state urinary excretion
during treatment with tablets. However, within-subject
coefficients of variation for urinary excretion during the
capsule and solution treatments exceeded between-
subject values.
Discussion
All currently available formulations of digoxin used
for oral administration (tablets, elixir) are variably and
incompletely absorbed from the gastrointestinal tract.l
One approach to formulation of oral digoxin prepara-
tions with improved bioavailability has been the de-
velopment of gelatin capsules containing a digoxin so-
lution. Studies of these capsules suggest that the bio-
availability of this digoxin preparation is greater and
more consistent than that of tablets and possibly of oral
digoxin solution.2-8
As is customary in current studies of digoxin bio-
availability,2*sJ3Js we utilized a slow intravenous infu-
sion as the reference standard for 100 percent systemic
availability. Because values for area under the concen-
tration curve and urinary excretion of digoxin after a
given intravenous dose are influenced by the rate of
infusion,z*so our estimates of absolute systemic avail-
ability of oral digoxin preparations apply specifically
to the 1 hour intravenous infusion standard. On the
basis of this reference system, our findings from the
single dose study indicate that the systemic availability
References
1. Gt’aWHaM
DJ,smfthNV, Koch-Weaer J: Bioavailabilii of drugs:
the dfgoxin dilemma. Clin Pharmacokin 1:36-51, 1976
2. Marcus FI, Mckemon J, PippIn S, et al: Digoxin bioavailability:
formulations and rates of infusions. Clin Pharmacol Ther 20:
253-259,1976
3. GhKti P, CaWnwzo 0, Madem 0, et al: Bioavailabilky of digoxin
in a new soluble pharmaceutical formulation in capsules. J Pharm
Sci 66:267-269, 1977
4. Johnron BP, SrMh Q, French J: The comparability of dosage
regimens of Lanoxin tablets and lanoxicaps. Br J Clin Pharmacol
4:209-211,1977
5. MaIlk Q, &hmlUl DH, Lbbdenbaum Jr Superior bioavailability of
digoxln solution in capsules. Clin Pharmacol Ther 18:761-766,
1976
6. Johnron BP, Bye C, Jone8 G, ei al: A completely absorbed oral
preparation of digoxin. Clin Pharmacol Ther 19:746-751, 1976
7. LMeebaum Jr Greater bioavailabilii of digoxin solution in cap-
sules. Clin Pharmacol Ther 21:278-282, 1977
a. BIdon PF: A comparison of the bioavailability of digoxin in cap-
sule, tablet, and solution taken orally with intravenous digoxin. J
July 1978
of the capsule preparation is significantly less than 100
percent. Furthermore, the rate and completeness of
digoxin absorption from capsules were essentially
identical to those of a standard digoxin solution. This
was evident from comparison of values for areas under
the plasma concentration curve or 24 hour urinary ex-
cretion of digoxin after single doses, as well as from
steady state plasma digoxin levels and urinary excretion
values on several consecutive days during long-term
therapy. Other reports2p6,s have suggested that ab-
sorption of the capsule preparation approaches 100
percent completeness and is greater than that of even
an oral solution. In any case, it is clear that the bio-
availability of digoxin capsules exceeds that of a stan-
dard reference tablet.s-s Finally, one study21 suggested
that between-subject variability in steady state serum
digoxin levels was less during treatment with capsules
than with tablets. However, our findings and those of
most other investigators2Jv5-s do not demonstrate a
striking or consistent difference among oral prepara-
tions in within- or between-subject coefficients of
variation of systemic availability after either single or
multiple doses.
Peak plasma digoxin levels after ingestion of the
various oral preparations tended to be highest with the
capsules. Anecdotal reports22 and other suggestions23
have associated high peak digoxin levels with the oc-
currence of transient cardiac arrhythmias, but sys-
tematic experimental study has revealed no such asso-
ciations.24 The clinical implications of the high peak
digoxin concentrations after ingestion of capsules re-
quire further study.
Acknowledgement
We are grateful for the collaboration of Dr. Dean S.
MacLaughlin (supported in part by U.S. Public Health
Service Grant GM-23430 to the Boston Collaborative
Drug Surveillance Program) and the editorial assistance
of Ms. Ann Werner.
Clin Pharmacol 16:461-467, 1976
9. Smith lW, Butler VP, Haber E: Determination of therapeutic and
toxic serum concentrations by radioimmunoassay. N Engl J Med
261:1212-1216,1969
10. Greenblatt DJ, Duhma DW, Koch-Weser J, et al: Evaluation of
digoxin bioavailability in single-dose studies. N Engl J Med 289:
651-654,1973
11. Usanis RA: NLIN-Nonlinear Least Squares Estimation of Pa-
rameters (Library Services Series Document no. LSR-089-1).
Research Triangle Park, North Carolina, Triangle Universities
Computation Center, 1972
12. Marcfuardt DW: An algorithm for least-squares estimation of
non&ear parameters. JSoc Ind Appl Math ?1:431-441, 1963
13. Greenbfatt DJ. Pfeffer HJ, O&s HR. et al: Pharmacokinetics of
quintdine in humans after fntravenous, intramuscular and oral ad-
ministration. J Pharmacol Exp Ther 202:365-378, 1977
14. Greanbfait DJ, KocfwWeeer Jr Clinical pharmacoklnetics. N Engl
J Med 293:702-705,964970, 1975
15. W+erJf%F w%nantals of Cllnical pharmacokinetics. Hamilton,
Illinois, Drug Intelligence Publications, 1975
The American Journal of CARDfOLOGY Volume 42 135
PHARMACOKINETICS AN0 BIOAVAILABILITY OF DIGOXIN-LLOYD ET AL.

16. Glbakli M, Per&r D: Pharmacokinetics. New York, Marcel Dekker, Clin Pharmacol Ther 15510~513, 1974
1975 2 1. Rodgor@
EM, Gob&e SM, Kenyon WI, et al: Evaluation of digoxin
17. Snedecor GW, Co&ran WO: Statistical Methods. Ames, Iowa, capsules In outpatients. Br Med J 3:234-235, 1977
University of Iowa Press, 1967 22. Mamlnem V, RebnI P, Pa&kale E: Transient cardiac arrhythmias
16. Greenblati DJ, Duhme DW, Koch-Weser J, et al: Comparison of after single daily maintenance doses of digoxin. Clin Pharmacol
one- and six-day urinary digoxin excretion in single-dose bio- Ther 20:266-268,1976
availability studies. Clin Pharmacol Ther 16:813-816, 1974 23. Harter JO, Bkelly JP, Steers AW: Digoxin-the regulatory view-
19. llsalo E: Clinical pharmacokinetics of digoxin. Clin Pharmacokin point. Circulation 49:395-398, 1974
2:1-16, 1977 24. Chapple DJ, Hughes R, Johnson BF: The relationship between
20. Greenblati DJ, Duhme DW, Koch-Weser J, et al: Intravenous di- cardlotoxicity and plasma dlgoxln concentration in cunscious dogs.
goxin as a bioavailabilii standard: slow infusion and rapid injection. Br J Pharmacol57:23-27, 1976

136 July 1976 The American Journal of CARDIOLOGY Volume 42