Eur J Clin Pharmacol (1992) 42:197--201 EuropeanJournalof ~ 1 3 ~ : ~ ( ~ ( ~ @ Springer-Verlag 1992
Effect of salbutamol on digoxin pharmacokinetics M. Edner 1,1".Jogestrand 1, and R. Dahlqvist 2 1 Department of Clinical Physiology, Karolinska Hospital, Stockholm, 2 Division of Clinical Pharmacology, University Hospital, Umegl,Sweden Received: December 17, 1990/Accepted in revised form: May 31, 1991
Summary. A single dose of the ]32-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the p h e n o m e n o n is a 132-adrenoceptormediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man. Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutatool, 4 gg- kg 1. h - 1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 gg- kg- 1, was given 20 rain after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the A U C 0-6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol c o m p a r e d to placebo treatment. The serum potassium concentration was significantly lower after salbutamol c o m p a r e d to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this m a y be secondary to a ~2-adrenoceptor-mediated increase in NaK-ATPase activity.
Key words: Digoxin, Salbutamol; serum, skeletal muscle digoxin, pharmacokinetics, drug interaction, serum potassium
Cardiac glycosides inhibit the m e m b r a n e sodium-potassium p u m p by binding to the enzyme system Na-K-ATPase, which is considered to be the "digitalis receptor" [1]. Beta2-adrenoceptor stimulation by salbutamol has b e e n shown to increase skeletal muscle N a - K - p u m p activity in the rat [2]. Salbutamol i. p. gave rise to a 60-80% increase in the concentration of 3H-ouabain in rat skeletal muscle, whereas the serum concentration fell by approximately 20% [3]. In previous studies in which salbutamol has been administered as a single therapeutic dose, either by i.v. injection or orally, to digitalized healthy volunteers, a decrease in serum digoxin concentration has been observed [4, 5]. Since that change has occurred without any significant increase in the skeletal muscle digoxin concentration, the possibility remains that increased elimination of the drug, perhaps caused by increased renal blood flow, which has been observed in dogs [6], might be the cause of the salbutamol-induced decrease in serum digoxin. The purpose of the present study was to investigate the effect of salbutamol on digoxin kinetics, including its distribution and elimination kinetics, and its uptake in skeletal muscle.
Subjects and methods Nine healthy men (aged 20-39 y) with normal resting ECGs, serum electrolytes and serum creatinine took part in the study, which was approved by the Ethics Committee of the Karolinska Hospital. The nature and purpose of the investigation were explained to the subjects, who gave their informed consent to it. The subjects were investigated on two separate occasions, 3-4 weeks apart. On examination days a catheter was inserted into a cubital vein and a single injection of digoxin 15 ~tg.kg ~b.w., was given over 5 min. Twenty rain before the digoxin injection an i. v. infusion of salbutamol 4 gg, kg ~.h-~ or saline (random order) was started. The infusion was given for 10 h whilst the subject rested in the supine position. The salbutamol infusion was preceded by oral salbutamol 2 mg t. i. d. for 2 days, succeeded by 4 mg t. i. d. for 2 days. The latter dose was also given for a further 3 days after the infusion. The infusion rate and oral dose were selected to yield about the same steady-state concentration of salbutamol, which has an anticipated bioavailability of about 50% after oral dosing [7, 8]. When saline was given, the subject ingested placebo tablets before and after the
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Effect of salbutamol on digoxin pharmacokinetics M. Edner 1,1".Jogestrand 1, and R. Dahlqvist 2 1 Department of Clinical Physiology, Karolinska Hospital, Stockholm, 2 Division of Clinical Pharmacology, University Hospital, Umegl,Sweden Received: December 17, 1990/Accepted in revised form: May 31, 1991
Summary. A single dose of the ]32-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the p h e n o m e n o n is a 132-adrenoceptormediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man. Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutatool, 4 gg- kg 1. h - 1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i.v. injection of digoxin 15 gg- kg- 1, was given 20 rain after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the A U C 0-6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol c o m p a r e d to placebo treatment. The serum potassium concentration was significantly lower after salbutamol c o m p a r e d to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this m a y be secondary to a ~2-adrenoceptor-mediated increase in NaK-ATPase activity.
Key words: Digoxin, Salbutamol; serum, skeletal muscle digoxin, pharmacokinetics, drug interaction, serum potassium
Cardiac glycosides inhibit the m e m b r a n e sodium-potassium p u m p by binding to the enzyme system Na-K-ATPase, which is considered to be the "digitalis receptor" [1]. Beta2-adrenoceptor stimulation by salbutamol has b e e n shown to increase skeletal muscle N a - K - p u m p activity in the rat [2]. Salbutamol i. p. gave rise to a 60-80% increase in the concentration of 3H-ouabain in rat skeletal muscle, whereas the serum concentration fell by approximately 20% [3]. In previous studies in which salbutamol has been administered as a single therapeutic dose, either by i.v. injection or orally, to digitalized healthy volunteers, a decrease in serum digoxin concentration has been observed [4, 5]. Since that change has occurred without any significant increase in the skeletal muscle digoxin concentration, the possibility remains that increased elimination of the drug, perhaps caused by increased renal blood flow, which has been observed in dogs [6], might be the cause of the salbutamol-induced decrease in serum digoxin. The purpose of the present study was to investigate the effect of salbutamol on digoxin kinetics, including its distribution and elimination kinetics, and its uptake in skeletal muscle.
Subjects and methods Nine healthy men (aged 20-39 y) with normal resting ECGs, serum electrolytes and serum creatinine took part in the study, which was approved by the Ethics Committee of the Karolinska Hospital. The nature and purpose of the investigation were explained to the subjects, who gave their informed consent to it. The subjects were investigated on two separate occasions, 3-4 weeks apart. On examination days a catheter was inserted into a cubital vein and a single injection of digoxin 15 ~tg.kg ~b.w., was given over 5 min. Twenty rain before the digoxin injection an i. v. infusion of salbutamol 4 gg, kg ~.h-~ or saline (random order) was started. The infusion was given for 10 h whilst the subject rested in the supine position. The salbutamol infusion was preceded by oral salbutamol 2 mg t. i. d. for 2 days, succeeded by 4 mg t. i. d. for 2 days. The latter dose was also given for a further 3 days after the infusion. The infusion rate and oral dose were selected to yield about the same steady-state concentration of salbutamol, which has an anticipated bioavailability of about 50% after oral dosing [7, 8]. When saline was given, the subject ingested placebo tablets before and after the
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