Effect of sulfasalazine on digoxin bioavailability Low levels of digoxin were noted in a patient receiving digoxin and su(fasalazine (SSA). Discontinuation of SSA resulted in a significant increase in serum digoxin levels. To determine whether or not SSA consistently interfered with the therapeutic effect of digoxin, both drugs were administered to 10 normal subjects in a crossover study. Each received 2 doses of digoxin (0.5 mg, elixir): one dose given alone, and a second dose after 6 days of treatment with SSA. When digoxin was given with SSA, the average area under the serum digoxin curve fell from the control value of 8.79 ng . hr . ml- 1 to 6.66 ng . hr . ml- 1 (p < 0.05), fell and total urinary excretion decreased from 278 mcg/IO days to 228 mcg/lO days (p < 0.025). These changes suggest interference with the bioavailability of digoxin by SSA. Studies were conducted to determine whether SSA inhibited digoxin absorption by physically absorbing the glycoside from solution. In vitro tests failed to reveal any significant adsorptive properties for SSA.
Randy P. Juhl, Ph.D., Robert W. Summers, M.D., J. K. Guillory, Ph.D., Seymour M. Blaug, Ph.D., Frank H. Cheng, Ph.D., and Donald D. Brown, M.D. Iowa City, Iowa College of Pharmacy and College ~l Medicine, University of Iowa
A number of studies concerning various aspects of digoxin pharmacokinetics have been published since the advent of the radioimmunoassay. These studies have shown that the bioavailability of digoxin is influenced by route of administration,l1, 35 dosage form,ll, 18, 30, 35 tablet dissolution rate,4, 8, 18, 20, 25, 30, 32, 35 and intestinal mucosal pathology. 12, 15, 21 Drugs have also been reported to interfere with the absorption of digoxin. Changes in gastrointestinal motility caused by cholinergic stimulation Supported in part by Grant Nos. 2MOI-RR-13, General Clinical Research Centers Branch, Division of Research Resources, National Institutes of Health, 73-12-32 from the Iowa Heart Association. and the Veterans Institutional Research Grant No. 10317. Received for publication April I, 1976. Accepted for publication June 14, 1976. Reprint requests to: Robert W. Summers, M.D., Division of Gastroenterology, Department of Internal Medicine, University Hospitals, Iowa City, Iowa 52242.
or blockage have been reported by Manninen and co-workers 27 , 28 to alter the absorption of poorly soluble digoxin tablets. Physical adsorption of digoxin by adsorbents has been demonstrated in vitro 3 , 22 and has been shown to decrease absorption in vivo. 3 , 6 Brown and Juhl 6 reported decreased absorption in man when digoxin was given with aluminum hydroxide, magnesium trisilicate, magnesium hydroxide, and a kaolin-pectin mixture. Several studies have demonstrated the binding of digoxin to the anion exchange resin, cholestyramine.1, 3, 10 The oral administration of neomycin may result in a sprue-like syndrome that may impair digoxin absorption. 26 Inexplicably low serum levels of digoxin were recently noted by the authors in a patient receiving digoxin and sulfasalazine (SSA). The present investigation was designed to study the
387
388
iuhl et al.
possible interference by SSA with the bioavailability of digoxin. Case report
A 49-yr-old white male patient with congestive heart failure secondary to cardiomyopathy was being treated with 0.25 mg per day of digoxin (Lanoxin). The patient was also taking 8 gm daily of sulfasalazine (Azulfidine) for Crohn's disease involving the terminal ileum, which at the time of this admission was well controlled. Therapy with both drugs was continued for a period of three months, at which time the patient's serum was assayed for digoxin by radioimmunoassay. Serum digoxin levels on this, and repeat determinations, was found to be under 0.4 ng/m!. Neither raising the digoxin dose to 0.50 mg/day nor switching from tablets to pediatric elixir resulted in therapeutic serum levels. Screening for malabsorption was performed. Five hours after 25 gm of D ( +)- xylose, 7.8 gm was excreted in the urine (normal, 6.5 gm ± 1.2 gm). Serum optical density (OD) 4 hr after fat load was 0.03 OD units (normal, >0.100 OD units).14 Separating the time of administration of the digoxin and the SSA by several hours failed to increase the serum digoxin levels, but after discontinuation of the SSA, serum digoxin levels rose to 0.9 - 1.1 ng/m!. The possibility that SSA or its primary metabolite, sulfapyridine, may have interfered with the radioimmunoassay of digoxin was considered. The addition of these drugs to serum samples containing known amounts of digoxin failed to affect the accuracy of the radioimmunoassay. Experimental procedure
Subjects. In order to investigate the possible effects of sulfasalazine on the absorption of digoxin, single-dose studies of bioavailability were performed on normal adult subjects. The subjects ranged in age from 20 to 36 yr and in weight from 50 to 91 kg. There were 7 males and 3 females. Prior to entry into the study, all subjects were screened and found to have normal cardiac, renal, hepatic, and absorptive functions as measured by electrocardiogram
Clinical Pharmacology and Therapeutics
(ECG), 24 hr endogenous creatinine clearance, CBC, SMA 12/60, serum carotene, and 5-hr D-xylose urinary excretion tests. Analytical methods. Serum samples were analyzed for digoxin in duplicate by radioimmunoassay (Schwarz/Mann). Urine samples were analyzed by a similar method aiter the addition of 1.0 ml of blank plasma to each sample. Acetylator phenotype was determined for 8 of the 10 subjects according to the method of Das and Eastwood. 7 Serum levels of free and acetylated sulfapyridine were determined spectrophotometrically.13 A ratio of free to acetylated sulfapyridine of greater than 1.9 is characteristic of the slow acetylator phenotype. A ratio of less than 1.9 defines fast acetylators. Drug administration. Two different treatments were administered to the subjects in a crossover fashion. The control treatment consisted of 0.5 ml digoxin in the form of an elixir (Lanoxin), 0.05 mg/m!. The experimental treatment consisted of 6 days* of pretreatment with SSA (Azulfidine), 500-mg tablets, followed by 0.5 mg of digoxin elixir. The order in which the two treatments were administered to the subjects was randomized. The first 4 subjects to participate in the study (L. 1.,1. L., M. C., and M. W.) took 2 gm of SSA daily in divided doses for 6 days and 0.5 gm of SSA 30 min before the digoxin dose on the morning of day 7. In an effort to more closely approximate the dosage of SSA of the patient in whom the interaction was first detected, the remaining 6 subjects followed a graduated dosage schedule, receiving SSA, 2 gm/day, on days 1 and 2, 4 gm/day on days 3 and 4, 6 gm/day on days 5 and 6, and 2 gm approximately 30 min before receiving digoxin on the morning of day 7. Digoxin elixir was administered with a syringe in order to deliver the solution to the back of the mouth and was followed by 240 ml of water. The subjects fasted for at least 8 hr prior to receiving digoxin and for 4 hr after the dose. Subjects were asked to refrain from taking other drugs or alcohol during the study. *The 6·day period is based on the assumption that a steady state had been achieved, as was reported by Schroder, H., and Campbell, D. E. S.: CUN. PHARMACOL. THER. 13:539·551, 1972.
Volume 20 Number 4
SulJasalazine and digoxin interaction
389
6
5 ~
g .s Ol
4
Z X
0
C)
3
_
Digoxin
-
Digoxin + Sulfasalazine
is ::2: ::J a: w U)
3
2
4
5
TIME (hours)
Fig. 1. Mean (±SEM) serum digoxin concentrations for all 10 subjects after administration of 0.5 mg digoxin alone and with sulfasalazine.
Sample collection. Venous blood samples were withdrawn at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 5.0, and 12 hr following each dose of digoxin. The IO-ml samples were allowed to clot. The serum was then removed, placed in a separate vial, and frozen at -4° C until assayed for digoxin. A duplicate O-hr sample was obtained for determination of acetylator phenotype when the subjects were taking sulfasalazine. Fractional urine samples were collected from to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 14 hr after the digoxin dose. Twenty-four hour urine samples were collected for an additional 9 days. At the end of each collection period, the total urine volume was recorded and a portion of the urine sample refrigerated until assayed for digoxin. Pharmacokinetic methods. Areas under the serum digoxin curves were calculated using the trapezoidal method. 29 The areas were calculated for the time period of to 5 hr after the dose. The 12-hr serum digoxin levels were, in most cases, below the limits of the assay and therefore were not included in the calculation of the areas under the curves. In all cases, serum curves revealed that there was no further significant absorption after 5 hr. Bioavailability was also estimated by comparison of total excretion of digoxin in the urine
°
°
over 10 days. Urinary excretion rate was calculated from the slope of the line plotting the logarithm of digoxin remaining to be excreted against time. Statistical methods. The pharmacokinetic parameters calculated from the two different treatments were compared by the use of a nonparametric method for a two-period crossover design as described by Koch. 23 Test procedures for hypotheses concerning direct effects, residual effects, and period effects were formulated in terms of Wilcoxon statistics. In vitro adsorption studies. To determine whether or not SSA physically adsorbed digoxin, 10 ml of a solution containing digoxin, 0.05 mcg/ml, and 3H-digoxin (New England Nuclear) were placed in clear plastic disposable test tubes. SSA powder, 0.5,1.0,2.0,4.0,6.0, or 8.0 mg/ml, was then added to the tubes. Experiments were performed in duplicate, and the results were averaged. The ratios of SSA to digoxin were similar to dosage ratios in subjects. The contents of the tubes were mixed periodically by shaking. After 30 min, the tubes were centrifuged to separate insoluble SSA from the supernate. Then, duplicate 0.025-ml aliquots were removed and added to vials containing 10 ml of scintillation fluid (Aqua-sol-2, New England Nuclear), and 3H activity was measured. Raw counts per minute were cor-
390
Juhl et al.
Clinical Pharmacology and Therapeutics
Table I. Areas under the serum digoxin curve, urinary excretion rates, and total urinary excretion over 10 days, for all subjects Area under serum digoxin curve (ng'hr'ml- l) Subject L. J. J. L. M.e. M.W. C. P. D. G. D. M. A. J. R. S. R. J. Mean ± SE
Digoxin alone 8.54 15.20 5.18 5.52 15.36 8.60 9.70 4.51 9.10 6.17
I
Digoxin with SSA 7.25 10.61 6.26 5.94 6.82 4.61 9.15 4.02 6.87 5.02
8.79 (1.22) 6.6 (0.64) P < 0.05
Urinary digoxin excretion rate (darl) Digoxin alone 0.468 0.421 0.373 0.404 0.381 0.401 0.428 0.396 0.404 0.410
I
Digoxin with SSA 0.405 0.398 0.345 0.396 0.370 0.430 0.418 0.340 0.431 0.458
0.409 (0.025) 0.399 (0.036) P > 0.05, NS
rected for quenching by comparison with external standard values and converted to disintegrations per minute. The number of disintegrations per minute of each sample containing SSA was compared to that of a control sample with no SSA. Experiments were carried out at pH 1.2S, 3.0, and 7.0. Results
Serum levels. The serum curves, the average serum digoxin concentrations for all 10 subjects, for digoxin given alone and with SSA are shown in Fig. 1. The rate at which digoxin was absorbed was similar for both. The time of the peak serum digoxin level and the shape of the curves are identical for digoxin given alone and digoxin given with SSA. There was some variation among the individual subjects in the slope of the absorption phase of the curves and in the time at which peak levels were reached, but no trend toward either delayed or accelerated absorption emerged. This is important because changes in the rate of absorption may alter the shape of the absorption curve such that the area under the curve method of estimating digoxin bioavailability may not be accurate. 30 The areas under the serum curve for each subject are shown in Table 1. The average area for digoxin given alone was 8.79 (±1.22, SEM) ng . hr . ml- l and for digoxin and SSA,
Total urinary digoxin (mcg) Digoxin alone 320 289 244 227 333 297 307 209 356 199
I
Digoxin with SSA
251 240 195 272 172 280 294 146 249 183
288.1 (15.1) 278.0 (16.4) P < 0.025
6.66 (±0.64, SEM) ng . ml . hr-l. This difference represents a decrease in area under the curve of 24.2% (T = 17, P < O.OS). The bioavailability of digoxin, as measured by area under the curve, was decreased in 8 of the 10 subjects when SSA was given. Two subjects (M. W. and M. C.) demonstrated an apparent increase in digoxin absorption when it was given with SSA. Changes in area under the curve ranged from an increase of 21 % to a decrease of S6%. Serum sulfapyridine levels and acetylator phenotypes were available for 8 of the 10 subjects. Three subjects were classified as fast acetylators and the remaining S as slow acetylators. No correlation was found between degree of digoxin malabsorption and serum sulfapyridine levels or acetylator phenotype. Urinary excretion. The average rates of urinary excretion of digoxin were similar for both treatments: 0.409 (±0.02S) day-l for digoxin given alone and 0.399 (±0.036) day-l for digoxin plus SSA. The excretion rate constants for each subject are shown in Table I. Total urinary digoxin excretion averaged 278.0 (± 16.4, SEM) mcg/1O days for digoxin alone and 228.1 (±IS.I, SEM) mcg/1O days for digoxin with SSA (Table I), an average decrease of 18.1% (T = 16, P < 0.02S). All subjects, with one exception (M. W.), excret-
Volume 20 Number 4
SulJasalazine and digoxin interaction
391
300 250
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X
0
(!)
150
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Randy P. Juhl, Ph.D., Robert W. Summers, M.D., J. K. Guillory, Ph.D., Seymour M. Blaug, Ph.D., Frank H. Cheng, Ph.D., and Donald D. Brown, M.D. Iowa City, Iowa College of Pharmacy and College ~l Medicine, University of Iowa
A number of studies concerning various aspects of digoxin pharmacokinetics have been published since the advent of the radioimmunoassay. These studies have shown that the bioavailability of digoxin is influenced by route of administration,l1, 35 dosage form,ll, 18, 30, 35 tablet dissolution rate,4, 8, 18, 20, 25, 30, 32, 35 and intestinal mucosal pathology. 12, 15, 21 Drugs have also been reported to interfere with the absorption of digoxin. Changes in gastrointestinal motility caused by cholinergic stimulation Supported in part by Grant Nos. 2MOI-RR-13, General Clinical Research Centers Branch, Division of Research Resources, National Institutes of Health, 73-12-32 from the Iowa Heart Association. and the Veterans Institutional Research Grant No. 10317. Received for publication April I, 1976. Accepted for publication June 14, 1976. Reprint requests to: Robert W. Summers, M.D., Division of Gastroenterology, Department of Internal Medicine, University Hospitals, Iowa City, Iowa 52242.
or blockage have been reported by Manninen and co-workers 27 , 28 to alter the absorption of poorly soluble digoxin tablets. Physical adsorption of digoxin by adsorbents has been demonstrated in vitro 3 , 22 and has been shown to decrease absorption in vivo. 3 , 6 Brown and Juhl 6 reported decreased absorption in man when digoxin was given with aluminum hydroxide, magnesium trisilicate, magnesium hydroxide, and a kaolin-pectin mixture. Several studies have demonstrated the binding of digoxin to the anion exchange resin, cholestyramine.1, 3, 10 The oral administration of neomycin may result in a sprue-like syndrome that may impair digoxin absorption. 26 Inexplicably low serum levels of digoxin were recently noted by the authors in a patient receiving digoxin and sulfasalazine (SSA). The present investigation was designed to study the
387
388
iuhl et al.
possible interference by SSA with the bioavailability of digoxin. Case report
A 49-yr-old white male patient with congestive heart failure secondary to cardiomyopathy was being treated with 0.25 mg per day of digoxin (Lanoxin). The patient was also taking 8 gm daily of sulfasalazine (Azulfidine) for Crohn's disease involving the terminal ileum, which at the time of this admission was well controlled. Therapy with both drugs was continued for a period of three months, at which time the patient's serum was assayed for digoxin by radioimmunoassay. Serum digoxin levels on this, and repeat determinations, was found to be under 0.4 ng/m!. Neither raising the digoxin dose to 0.50 mg/day nor switching from tablets to pediatric elixir resulted in therapeutic serum levels. Screening for malabsorption was performed. Five hours after 25 gm of D ( +)- xylose, 7.8 gm was excreted in the urine (normal, 6.5 gm ± 1.2 gm). Serum optical density (OD) 4 hr after fat load was 0.03 OD units (normal, >0.100 OD units).14 Separating the time of administration of the digoxin and the SSA by several hours failed to increase the serum digoxin levels, but after discontinuation of the SSA, serum digoxin levels rose to 0.9 - 1.1 ng/m!. The possibility that SSA or its primary metabolite, sulfapyridine, may have interfered with the radioimmunoassay of digoxin was considered. The addition of these drugs to serum samples containing known amounts of digoxin failed to affect the accuracy of the radioimmunoassay. Experimental procedure
Subjects. In order to investigate the possible effects of sulfasalazine on the absorption of digoxin, single-dose studies of bioavailability were performed on normal adult subjects. The subjects ranged in age from 20 to 36 yr and in weight from 50 to 91 kg. There were 7 males and 3 females. Prior to entry into the study, all subjects were screened and found to have normal cardiac, renal, hepatic, and absorptive functions as measured by electrocardiogram
Clinical Pharmacology and Therapeutics
(ECG), 24 hr endogenous creatinine clearance, CBC, SMA 12/60, serum carotene, and 5-hr D-xylose urinary excretion tests. Analytical methods. Serum samples were analyzed for digoxin in duplicate by radioimmunoassay (Schwarz/Mann). Urine samples were analyzed by a similar method aiter the addition of 1.0 ml of blank plasma to each sample. Acetylator phenotype was determined for 8 of the 10 subjects according to the method of Das and Eastwood. 7 Serum levels of free and acetylated sulfapyridine were determined spectrophotometrically.13 A ratio of free to acetylated sulfapyridine of greater than 1.9 is characteristic of the slow acetylator phenotype. A ratio of less than 1.9 defines fast acetylators. Drug administration. Two different treatments were administered to the subjects in a crossover fashion. The control treatment consisted of 0.5 ml digoxin in the form of an elixir (Lanoxin), 0.05 mg/m!. The experimental treatment consisted of 6 days* of pretreatment with SSA (Azulfidine), 500-mg tablets, followed by 0.5 mg of digoxin elixir. The order in which the two treatments were administered to the subjects was randomized. The first 4 subjects to participate in the study (L. 1.,1. L., M. C., and M. W.) took 2 gm of SSA daily in divided doses for 6 days and 0.5 gm of SSA 30 min before the digoxin dose on the morning of day 7. In an effort to more closely approximate the dosage of SSA of the patient in whom the interaction was first detected, the remaining 6 subjects followed a graduated dosage schedule, receiving SSA, 2 gm/day, on days 1 and 2, 4 gm/day on days 3 and 4, 6 gm/day on days 5 and 6, and 2 gm approximately 30 min before receiving digoxin on the morning of day 7. Digoxin elixir was administered with a syringe in order to deliver the solution to the back of the mouth and was followed by 240 ml of water. The subjects fasted for at least 8 hr prior to receiving digoxin and for 4 hr after the dose. Subjects were asked to refrain from taking other drugs or alcohol during the study. *The 6·day period is based on the assumption that a steady state had been achieved, as was reported by Schroder, H., and Campbell, D. E. S.: CUN. PHARMACOL. THER. 13:539·551, 1972.
Volume 20 Number 4
SulJasalazine and digoxin interaction
389
6
5 ~
g .s Ol
4
Z X
0
C)
3
_
Digoxin
-
Digoxin + Sulfasalazine
is ::2: ::J a: w U)
3
2
4
5
TIME (hours)
Fig. 1. Mean (±SEM) serum digoxin concentrations for all 10 subjects after administration of 0.5 mg digoxin alone and with sulfasalazine.
Sample collection. Venous blood samples were withdrawn at 0, 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, 3.0, 5.0, and 12 hr following each dose of digoxin. The IO-ml samples were allowed to clot. The serum was then removed, placed in a separate vial, and frozen at -4° C until assayed for digoxin. A duplicate O-hr sample was obtained for determination of acetylator phenotype when the subjects were taking sulfasalazine. Fractional urine samples were collected from to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 14 hr after the digoxin dose. Twenty-four hour urine samples were collected for an additional 9 days. At the end of each collection period, the total urine volume was recorded and a portion of the urine sample refrigerated until assayed for digoxin. Pharmacokinetic methods. Areas under the serum digoxin curves were calculated using the trapezoidal method. 29 The areas were calculated for the time period of to 5 hr after the dose. The 12-hr serum digoxin levels were, in most cases, below the limits of the assay and therefore were not included in the calculation of the areas under the curves. In all cases, serum curves revealed that there was no further significant absorption after 5 hr. Bioavailability was also estimated by comparison of total excretion of digoxin in the urine
°
°
over 10 days. Urinary excretion rate was calculated from the slope of the line plotting the logarithm of digoxin remaining to be excreted against time. Statistical methods. The pharmacokinetic parameters calculated from the two different treatments were compared by the use of a nonparametric method for a two-period crossover design as described by Koch. 23 Test procedures for hypotheses concerning direct effects, residual effects, and period effects were formulated in terms of Wilcoxon statistics. In vitro adsorption studies. To determine whether or not SSA physically adsorbed digoxin, 10 ml of a solution containing digoxin, 0.05 mcg/ml, and 3H-digoxin (New England Nuclear) were placed in clear plastic disposable test tubes. SSA powder, 0.5,1.0,2.0,4.0,6.0, or 8.0 mg/ml, was then added to the tubes. Experiments were performed in duplicate, and the results were averaged. The ratios of SSA to digoxin were similar to dosage ratios in subjects. The contents of the tubes were mixed periodically by shaking. After 30 min, the tubes were centrifuged to separate insoluble SSA from the supernate. Then, duplicate 0.025-ml aliquots were removed and added to vials containing 10 ml of scintillation fluid (Aqua-sol-2, New England Nuclear), and 3H activity was measured. Raw counts per minute were cor-
390
Juhl et al.
Clinical Pharmacology and Therapeutics
Table I. Areas under the serum digoxin curve, urinary excretion rates, and total urinary excretion over 10 days, for all subjects Area under serum digoxin curve (ng'hr'ml- l) Subject L. J. J. L. M.e. M.W. C. P. D. G. D. M. A. J. R. S. R. J. Mean ± SE
Digoxin alone 8.54 15.20 5.18 5.52 15.36 8.60 9.70 4.51 9.10 6.17
I
Digoxin with SSA 7.25 10.61 6.26 5.94 6.82 4.61 9.15 4.02 6.87 5.02
8.79 (1.22) 6.6 (0.64) P < 0.05
Urinary digoxin excretion rate (darl) Digoxin alone 0.468 0.421 0.373 0.404 0.381 0.401 0.428 0.396 0.404 0.410
I
Digoxin with SSA 0.405 0.398 0.345 0.396 0.370 0.430 0.418 0.340 0.431 0.458
0.409 (0.025) 0.399 (0.036) P > 0.05, NS
rected for quenching by comparison with external standard values and converted to disintegrations per minute. The number of disintegrations per minute of each sample containing SSA was compared to that of a control sample with no SSA. Experiments were carried out at pH 1.2S, 3.0, and 7.0. Results
Serum levels. The serum curves, the average serum digoxin concentrations for all 10 subjects, for digoxin given alone and with SSA are shown in Fig. 1. The rate at which digoxin was absorbed was similar for both. The time of the peak serum digoxin level and the shape of the curves are identical for digoxin given alone and digoxin given with SSA. There was some variation among the individual subjects in the slope of the absorption phase of the curves and in the time at which peak levels were reached, but no trend toward either delayed or accelerated absorption emerged. This is important because changes in the rate of absorption may alter the shape of the absorption curve such that the area under the curve method of estimating digoxin bioavailability may not be accurate. 30 The areas under the serum curve for each subject are shown in Table 1. The average area for digoxin given alone was 8.79 (±1.22, SEM) ng . hr . ml- l and for digoxin and SSA,
Total urinary digoxin (mcg) Digoxin alone 320 289 244 227 333 297 307 209 356 199
I
Digoxin with SSA
251 240 195 272 172 280 294 146 249 183
288.1 (15.1) 278.0 (16.4) P < 0.025
6.66 (±0.64, SEM) ng . ml . hr-l. This difference represents a decrease in area under the curve of 24.2% (T = 17, P < O.OS). The bioavailability of digoxin, as measured by area under the curve, was decreased in 8 of the 10 subjects when SSA was given. Two subjects (M. W. and M. C.) demonstrated an apparent increase in digoxin absorption when it was given with SSA. Changes in area under the curve ranged from an increase of 21 % to a decrease of S6%. Serum sulfapyridine levels and acetylator phenotypes were available for 8 of the 10 subjects. Three subjects were classified as fast acetylators and the remaining S as slow acetylators. No correlation was found between degree of digoxin malabsorption and serum sulfapyridine levels or acetylator phenotype. Urinary excretion. The average rates of urinary excretion of digoxin were similar for both treatments: 0.409 (±0.02S) day-l for digoxin given alone and 0.399 (±0.036) day-l for digoxin plus SSA. The excretion rate constants for each subject are shown in Table I. Total urinary digoxin excretion averaged 278.0 (± 16.4, SEM) mcg/1O days for digoxin alone and 228.1 (±IS.I, SEM) mcg/1O days for digoxin with SSA (Table I), an average decrease of 18.1% (T = 16, P < 0.02S). All subjects, with one exception (M. W.), excret-
Volume 20 Number 4
SulJasalazine and digoxin interaction
391
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