Digoxin-verapamil interaction: Reduction of biliary but not renal digoxin clearance in humans The interaction between digoxin and verapamil was studied in six patients (mean age -± SD, 61 -± 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady-state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady-state plasma concentrations of digoxin, from 0.80 ± 0.24 to 1.15 -± 0.40 nmol/L (p < 0.01). The biliary clearance of digoxin decreased by 43%, from 187 ±. 89 to 101 -± 55 ml/min (p < 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 -± 31 versus 173 -± 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route. (CLIN PFIARMACOL TREK 1991;49:256-62.)
Ann Hedman, MScPharm, Bo Angelin, MD, PhD, Annie Arvidsson, Dr Med Sci, Olof Beck, PhD, Rune Dahlqvist, MD, PhD, Bengt Nilsson, MD, Margareta Olsson, MD, and Karin Schenck-Gustafsson, MD, PhD Huddinge and Stockholm, Sweden
A clinically important pharmacokinetic interaction between the calcium antagonist verapamil and digoxin has been reported in several studies. During maintenance treatment, verapamil has been shown to cause a significant elevation of the steady-state plasma concentrations of digoxin." Verapamil was also shown to decrease the total clearance of digoxin after a single intravenous dose of the glycoside.7-9 Conflicting results have been presented concerning the mechanisms involved in this interaction. Reductions of both renal and nonrenal clearance of digoxin have been reported. Pedersen et a1.19 demonstrated an initial verapamil-induced reduction in renal clearance of digoxin after 1 week of treatment, disappearing after 6 weeks of treatment in the same subjects. Other studies have reported verapamil to decrease the renal
From the Departments of Clinical Pharmacology, Medicine, and Radiology, Metabolism Unit, Karolinska Institute at Huddinge University Hospital, and the Departments of Clinical Pharmacology and Medicine, Karolinska Hospital. Supported by grants from the Swedish Medical Research Council, Stockholm, Sweden (04X-3902 and 03X-4793) and the Karolinska Institute, Stockholm. Received for publication May 9, 1990; accepted Oct. 15, 1990. Reprint requests: Ann Hedman, MScPharm, Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden. 13/1/26118
256
clearance of digoxin by 21% to 53%.2.4.7 On the other hand, two recent reports suggested that verapamil decreases solely the nonrenal clearance without influencing the renal clearance of digoxin." In two previous studies in patients" and healthy volunteers, /2 we found that quinidine, in addition to its inhibition of the renal digoxin clearance, also decreases the biliary excretion of this compound. We have now examined the effects of verapamil on biliary clearance during steady state and compared it directly with its effect on renal clearance of digoxin.
MATERIAL AND METHODS Patients. Six patients with chronic atrial fibrillation were included in the study after informed consent was obtained. They were receiving maintenance treatment of digoxin only or a combination of digoxin and verapamil. Patient characteristics, concomitant chronic medication (which was kept unchanged throughout the study), and the daily doses of digoxin and verapamil are given in Table I. No patient had abnormalities of renal or hepatic function (as indicated by serum transaminase and serum creatinine values). Protocol. The renal and biliary clearances of digoxin were determined twice during steady state in a crossover fashion. For the first investigation period, three of the patients were receiving maintenance treatment of digoxin only, whereas the other three patients
VOLUME 49 NUMBER 3
Digoxin-verapamil interaction
257
Table I. Patient characteristics, administration, and medications Patient No.
Sex
Age (yr)
1
F
2
Body weight (kg)
Diagnoses
62
106
Atrial fibrillation, hypertension
M
69
84
3
M
56
74
4
M
61
114
5
M
56
84
6
M
60
80
Atrial fibrillation, diabetes Atrial fibrillation Atrial fibrillation, hypertension Atrial fibrillation, hypertension Atrial fibrillation
Verapamil dose
Digoxin dose (mg)
(mg t.i.d.)
0.25
0.25
80
bid.
80
Crossover fashion
Concomitant medication Bendroflumethiazide, furosemide, potassium chloride, warfarin Chlorpropamide, warfarin Warfarin
0.25
80
0.38
80
Amiloride, hydrochlorothiazide
0.38
80
Warfarin
0.38
80
Warfarin
Ii
I
D + V
D + V
D + V
D
+ V
D
D
D + V
D + V
D
D, Digoxm; V. verapam 1.
were receiving combined digoxin-verapamil treatment (Table I). All patients had received digoxin only or the combination of digoxin and verapamil in fixed doses for at least 4 weeks before the clearance determinations. The dose of digoxin (Lanacrist; Astra Lakemedel AB, Sodertalje, Sweden) was the same (0.25 to 0.50 mg orally daily) during both periods. Verapamil was given as conventional tablets, 80 mg t.i.d (Isoptin [verapamil hydrochloride]; Meda AB, Goteborg, Sweden). After an interval of at least 2 weeks, the second investigation was performed. On the study day no digoxin was taken. The biliary-excreted digoxin was collected by a modified duodenal-marker-perfusion technique)1,13,14 Verapamil was administered in the morning to the fasting patient before the triple-lumen polyvinyl tube was inserted oropharyngeally under fluoroscopic control. The tube was positioned in the duodenum with the infusion site at the level of the ampulla of Vater and the proximal and distal collecting ports 2 and 12 cm farther distally. An infusion mixture was prepared of 5% glucose and amino acids (Vamin; KabiVitrum, Stockholm, Sweden), to which essential amino acids (L-methionine, 40 mmol/L; L-valine, 25.8 mmol/L; and L-phenylalanine, 18.2 mmol/L) and sulfobromophthalein sodium (Bromsulphalein) as a nonabsorbable marker had been added. This mixture was infused constantly through the tube into the duodenum at a
rate of 5 ml/min for 6 to 8 hours. Continuous aspiration of bile was started simultaneously, and after an equilibration period, hourly samples of 10 ml bile were drawn from the two collecting ports. Urine was collected in parallel hourly fractions, and venous blood samples were taken at the midpoint of the intervals. The Ethics Committee of Huddinge University Hospital approved of the study. Analyses. The concentrations of digoxin were determined in plasma, urine, and bile aspirates by radioimmunoassay (Becton-Dickinson and Co., Orangeburg, N.Y.) after dilution with blank plasma. Endogenous constituents in the bile at these dilutions did not interfere with the digoxin assay. The interassay variation of the means of duplicate digoxin determinations in plasma was 8% and 6% (1.2 and 2.3 nmol/L, respectively), and the intra-assay variation was 5% and 3% (1.0 and 3.7 nmol/L, respectively; n = 15). The limit of determinat ion was 0.5 nmol/L. The concentrations of norverapamil and the (+)Rand ()S-enantiomers of verapamil in plasma were determined by a specific HPLC method. Plasma samples were prepared for the chiral analysis by a solvent extraction procedure as follows: An aliquot (1.0 ml) of plasma was added to a glass test tube together with 0.5 ml NaOH (1 mol/L) and 3.5 ml n-hexane contain-
CLIN PHARMACOL THER MARCH 1991
258 Hedman et al.
Table II. Steady-state digoxin kinetics in six patients during digoxin treatment only or concomitant treatment with verapamil Plasma concentration of digoxin (nmollL) D + V % Change
Patient
0.86 ± 1.20 ± 0.53 ± 0.87 ± 0.65 ± 0.66 ± 0.80 ±
2 3
4 5
6
Mean ± SD
0.12 0.29 0.05 0.06
1.05 ± 0.20 1.90 ± 0.33
22 58 57 39 65
0.83 ± 0.14 1.21 ± 0.20 1.07 ± 0.18 0.82 ± 0.09 1.15 ± 0.40
0.11
0.05 0.24
24
44 ± 18
p Value*
Renal clearance (ml/mm) D + V % Change ± ± ± ± ± ± 153 ±
102 149 146 180 149 192
30 74 18
46 21
76 31
Ann Hedman, MScPharm, Bo Angelin, MD, PhD, Annie Arvidsson, Dr Med Sci, Olof Beck, PhD, Rune Dahlqvist, MD, PhD, Bengt Nilsson, MD, Margareta Olsson, MD, and Karin Schenck-Gustafsson, MD, PhD Huddinge and Stockholm, Sweden
A clinically important pharmacokinetic interaction between the calcium antagonist verapamil and digoxin has been reported in several studies. During maintenance treatment, verapamil has been shown to cause a significant elevation of the steady-state plasma concentrations of digoxin." Verapamil was also shown to decrease the total clearance of digoxin after a single intravenous dose of the glycoside.7-9 Conflicting results have been presented concerning the mechanisms involved in this interaction. Reductions of both renal and nonrenal clearance of digoxin have been reported. Pedersen et a1.19 demonstrated an initial verapamil-induced reduction in renal clearance of digoxin after 1 week of treatment, disappearing after 6 weeks of treatment in the same subjects. Other studies have reported verapamil to decrease the renal
From the Departments of Clinical Pharmacology, Medicine, and Radiology, Metabolism Unit, Karolinska Institute at Huddinge University Hospital, and the Departments of Clinical Pharmacology and Medicine, Karolinska Hospital. Supported by grants from the Swedish Medical Research Council, Stockholm, Sweden (04X-3902 and 03X-4793) and the Karolinska Institute, Stockholm. Received for publication May 9, 1990; accepted Oct. 15, 1990. Reprint requests: Ann Hedman, MScPharm, Department of Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Sweden. 13/1/26118
256
clearance of digoxin by 21% to 53%.2.4.7 On the other hand, two recent reports suggested that verapamil decreases solely the nonrenal clearance without influencing the renal clearance of digoxin." In two previous studies in patients" and healthy volunteers, /2 we found that quinidine, in addition to its inhibition of the renal digoxin clearance, also decreases the biliary excretion of this compound. We have now examined the effects of verapamil on biliary clearance during steady state and compared it directly with its effect on renal clearance of digoxin.
MATERIAL AND METHODS Patients. Six patients with chronic atrial fibrillation were included in the study after informed consent was obtained. They were receiving maintenance treatment of digoxin only or a combination of digoxin and verapamil. Patient characteristics, concomitant chronic medication (which was kept unchanged throughout the study), and the daily doses of digoxin and verapamil are given in Table I. No patient had abnormalities of renal or hepatic function (as indicated by serum transaminase and serum creatinine values). Protocol. The renal and biliary clearances of digoxin were determined twice during steady state in a crossover fashion. For the first investigation period, three of the patients were receiving maintenance treatment of digoxin only, whereas the other three patients
VOLUME 49 NUMBER 3
Digoxin-verapamil interaction
257
Table I. Patient characteristics, administration, and medications Patient No.
Sex
Age (yr)
1
F
2
Body weight (kg)
Diagnoses
62
106
Atrial fibrillation, hypertension
M
69
84
3
M
56
74
4
M
61
114
5
M
56
84
6
M
60
80
Atrial fibrillation, diabetes Atrial fibrillation Atrial fibrillation, hypertension Atrial fibrillation, hypertension Atrial fibrillation
Verapamil dose
Digoxin dose (mg)
(mg t.i.d.)
0.25
0.25
80
bid.
80
Crossover fashion
Concomitant medication Bendroflumethiazide, furosemide, potassium chloride, warfarin Chlorpropamide, warfarin Warfarin
0.25
80
0.38
80
Amiloride, hydrochlorothiazide
0.38
80
Warfarin
0.38
80
Warfarin
Ii
I
D + V
D + V
D + V
D
+ V
D
D
D + V
D + V
D
D, Digoxm; V. verapam 1.
were receiving combined digoxin-verapamil treatment (Table I). All patients had received digoxin only or the combination of digoxin and verapamil in fixed doses for at least 4 weeks before the clearance determinations. The dose of digoxin (Lanacrist; Astra Lakemedel AB, Sodertalje, Sweden) was the same (0.25 to 0.50 mg orally daily) during both periods. Verapamil was given as conventional tablets, 80 mg t.i.d (Isoptin [verapamil hydrochloride]; Meda AB, Goteborg, Sweden). After an interval of at least 2 weeks, the second investigation was performed. On the study day no digoxin was taken. The biliary-excreted digoxin was collected by a modified duodenal-marker-perfusion technique)1,13,14 Verapamil was administered in the morning to the fasting patient before the triple-lumen polyvinyl tube was inserted oropharyngeally under fluoroscopic control. The tube was positioned in the duodenum with the infusion site at the level of the ampulla of Vater and the proximal and distal collecting ports 2 and 12 cm farther distally. An infusion mixture was prepared of 5% glucose and amino acids (Vamin; KabiVitrum, Stockholm, Sweden), to which essential amino acids (L-methionine, 40 mmol/L; L-valine, 25.8 mmol/L; and L-phenylalanine, 18.2 mmol/L) and sulfobromophthalein sodium (Bromsulphalein) as a nonabsorbable marker had been added. This mixture was infused constantly through the tube into the duodenum at a
rate of 5 ml/min for 6 to 8 hours. Continuous aspiration of bile was started simultaneously, and after an equilibration period, hourly samples of 10 ml bile were drawn from the two collecting ports. Urine was collected in parallel hourly fractions, and venous blood samples were taken at the midpoint of the intervals. The Ethics Committee of Huddinge University Hospital approved of the study. Analyses. The concentrations of digoxin were determined in plasma, urine, and bile aspirates by radioimmunoassay (Becton-Dickinson and Co., Orangeburg, N.Y.) after dilution with blank plasma. Endogenous constituents in the bile at these dilutions did not interfere with the digoxin assay. The interassay variation of the means of duplicate digoxin determinations in plasma was 8% and 6% (1.2 and 2.3 nmol/L, respectively), and the intra-assay variation was 5% and 3% (1.0 and 3.7 nmol/L, respectively; n = 15). The limit of determinat ion was 0.5 nmol/L. The concentrations of norverapamil and the (+)Rand ()S-enantiomers of verapamil in plasma were determined by a specific HPLC method. Plasma samples were prepared for the chiral analysis by a solvent extraction procedure as follows: An aliquot (1.0 ml) of plasma was added to a glass test tube together with 0.5 ml NaOH (1 mol/L) and 3.5 ml n-hexane contain-
CLIN PHARMACOL THER MARCH 1991
258 Hedman et al.
Table II. Steady-state digoxin kinetics in six patients during digoxin treatment only or concomitant treatment with verapamil Plasma concentration of digoxin (nmollL) D + V % Change
Patient
0.86 ± 1.20 ± 0.53 ± 0.87 ± 0.65 ± 0.66 ± 0.80 ±
2 3
4 5
6
Mean ± SD
0.12 0.29 0.05 0.06
1.05 ± 0.20 1.90 ± 0.33
22 58 57 39 65
0.83 ± 0.14 1.21 ± 0.20 1.07 ± 0.18 0.82 ± 0.09 1.15 ± 0.40
0.11
0.05 0.24
24
44 ± 18
p Value*
Renal clearance (ml/mm) D + V % Change ± ± ± ± ± ± 153 ±
102 149 146 180 149 192
30 74 18
46 21
76 31
