EurJ ClinPharmacol(1992) 43:547-550
©
Springer-Verlag 1.992
Exercise and the pharmacokinetics of propranolol, verapamil and atenolol M.A. van Baak, J. M. V. Mooij, and E M. Ho Schiffers Departments of Pharmacolegyand Internal Medicine,Universityof Limburg,Maastricht,The Netherlands Received:December4, 1991/Acceptedin revisedform:April 22, 1992
Summary. The volumes of distribution of the fl-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated, Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70 % of maximal aerobic power were compared after i week of oral treatment (propranolol 80 mg b.d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50 % of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamit was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion. The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study. From the results it is concluded that exercise led to a reduction in the volume of distribution ofpropranolol during prolonged exercise (25 rain) at 70 % W .... which was not clearly demonstrable during 10 rain exercise at 50 % Wm,x. The volume of distribution of verapamil was reduced during 10 min exercise at 50 % W .... No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise. Key words: Propranolol, Atenolol, Verapamil; pharmacokinetics, exercise
Exercise influences a number of physiological factors that may affect the pharmacokinetics of drugs, including haemodynamics, metabolism, pH, temperature and gastro-intestinal function [Van Baak 1990]. A previous study showed that prolonged low intensity exercise significantly
reduced the half-life (tl/2) of the fl-adrenoceptor blocking agent propranolol [Arends et al. 1986]. On the other hand, the t~/2of the calcium antagonist verapamil was not significantly affected by prolonged moderate exercise [Mooij et al. 1986]. These findings were unexpected, since both drugs show flow-dependent extraction by the liver. In both studies liver blood flow, estimated by indocyanine green clearance, was significantly reduced during exercise. Thus an increase rather than a fall or a lack of change in tl/2 was expected. The fact that no increase in t~tzwas found might be explained by a concomitant reduction in the volume of distribution (V) during exercise. Hurwitz et al. (1983) showed that the plasma concentration of propranolot after oral administration was increased during exercise and suggested that V of propranolol might be reduced during exercise. The present study was done to investigate changes in the V of propranolol, atenolol and verapamil during exercise. Propranolol and verapamil are both lipophilic drugs, with high plasma protein binding and a high hepatic extraction ratio, while atenolol is hydrophilic, shows low plasma protein binding and is eliminated by the kidneys [Goodman et al. 1990].
Subjects and methods Two separate studieswere performed.In the firstthe drugswere administeredorally,and in the secondintravenously.
Subjects The firststudywas done 12healthy,male volunteers(age20 to 27 y); in the secondstudy7 healthyvolunteers(age20 to 23 y;3 m, 4 f) took part. The protocoI of the studies was approved by the Ethics Committee of the Universityof Limburg,and all subjectsgavetheir written informedconsentto it.
Protocol of the studies The first studywas peformedas part of a largerstudyof the effectsof ~-adrenoceptor blockers on endurance exercise performance.The subjects came to the laboratory three times. On the first occasion
548 350 E
0
250
propranolol atenolol
O o
150
~rest--
50 -40
~exercise~
[
I
-20
0
•
time
aI. 1987]. For atenolol the procedure was: after addition of 1N NaOH 200 gl and 250 ng procainamide, as internal standard, to 1 ml plasma, the plasma was extracted with 6ml dichloromethane:l-butanol (19:1). The organic phase was dried in a water bath under N2 and the residue dissolved in 100 gl eluent methanol:water:acetic acid:Bic B-7 (23:75:0.8:1.5). The solution was subjected to HPLC with a gBondapack C18 column (Waters Inc., The Netherlands). For fluorimetric detection the excitation wavelength was set at 222 nm and the emission filter at 320 nm. The interassay coefficient of variation of the procedure was 6.2 %.
rec
i
i
20
40
i
0
I
10
(mln)
Fig.l. Plasma concentrations of propranolot and atenolot at rest, during exercise, and during recovery (rec) after i week of oral administration (mean + SEM)
maximal aerobic power (W,,,~) on a cycle ergometer (Lode, Groningen, The Netherlands) was determined in an incremental exercise test done to exhaustion. Before the :next two visits, the subjects were given either propranolol (80 mg b. d.) or atenolol (100 mg) p. o. each for one week, in random order. The subjects took the last dose 1 h before coming to the laboratory. Treatment periods were separated by at least one drug-free week. On arrival in the laboratory catheters were inserted into forearm veins in each arm. A continuous infusion of saline (2.5 ml. rain ~)was started and was continued until the end of the recovery period. After 30 min at rest, the subject performed a submaximal endurance exercise test at 70 % Wm~ until exhaustion. Before and after the initial 30 min rest period (t = -30 and 0 rain), after l0 and 20 min of exercise (t = 10 and 20 min), at the moment of exhaustion, and after 3, 6 and 10 min of recovery, venous blood samples were obtained for determination of haematocrit haemoglobin concentration, and plasma drug concentration. In the second study all subjects came to the laboratory three times after an overnight fast. On each occasion the subjects were given an intravenous infusion: propranolol, atenolol or verapamil, in random order. There was an interval of at least I week between tests. After arrival in the laboratory venous catheters were inserted into forearm veins in each arm. A bolus injection of the drug (propranolo1195 gg. kg 1;verapami1225 gg. kg- 1;atenolo135 gg. kg a) was administered over 5 rain, followed by continuous infusion (propranotol 42 gg. min-1; verapamil 60 gg. min- ~; atenolol 5 gg- min- ~) until the end of the experiment. The doses of the bolus and the infusion were chosen to obtain steady-state plasma concentrations of the three drugs of approximately 50 ng.ml-L After 90 rain of the infusion, an incremental exercise test to exhaustion was performed on a cycle ergometer (Lode, Groningen, The Netherlands) to determine the maximal aerobic work capacity (Wm~). After further 60 rain at rest, the subject exercised for 10 min on the cycle ergometer at 50 % of Wmax, Venous blood samples for determination of the plasma concentrations of the drugs were obtained after 150,175 and 180 min of the infusion (t = -30,-15 and 0 min), and during the 1st, 3rd, 5th and 10th rain of exercise (t=l, 3, 5, 10min) and recovery ( t = l l , 13, 15, 20 min). Haematocrit and haemoglobin concentrations were also measured.
Methods Haemoglobin concentration was determined with the OSM2 haemoximeter (Radiometer, Copenhagen) and haematocrit by micro-centrifugation. From changes in haemoglobin and haematocrit, changes in plasma volume were calculated [Dill and Costill 1974]. Propranolol, verapamil and atenolol concentrations were determined by HPLC with fluorimetric detection. The methods for propranolol and verapamil have previously been described [Mooij et
Data analysis Data are presented as mean with (SD). Statistical analysis was performed by two-tailed Student t-tests for paired observations. In the second study analysis of variance with repeated measurements was used to analyze differences between the three drugs; post-hoc pairwise comparisons between drug treatments were performed by Scheffe's F-test. P < 0.05 was considered statistically significant.
Results
Plasma concentrations of p r o p r a n o l o l and atenolol in the first study are shown in Fig. 1. The plasma concentration of p r o p r a n o l o l did not Change significantly b e t w e e n t = - 3 0 min and t = 0 min (Fig. 1). Similar results were o b t a i n e d for the plasma atenolol concentration. D u r i n g exercise, however, the plasma concentration of propranolol rose significantly, f r o m 168 ( 1 1 3 ) n g - m l ~ to 202 (125) ng. m l - t at 20 rain exercise (P -- 0.01). I n contrast, the plasma c o n c e n t r a t i o n of atenolol did not change during exercise [265 ( l l 5 ) ng.m1-1 at t = 0 m i n and 270 (100) ng. m l - 1 at t = 20 mini (Fig. 1). Within the 10 min recovery period, the plasma p r o p r a n o l o l c o n c e n t r a t i o n had r e t u r n e d to the pre-exercise level. T h e plasma atenolol concentration, on the o t h e r hand, rose during the recovery period [from 267 (100) ng/ml at exhaustion to 292 (107) ng. ml 1at 6 min recovery, P = 0.01). T h e changes in the plasma v o l u m e during exercise were within 5 % after each drug. C o r r e c t i o n of the plasma concentration of the drug for the change in plasma volume did not yield significantly different results. T h e results of the incremental maximal exercise test in the s e c o n d study were: maximal heart rate was 144 (9) b e a t s . m i n - 1 during propranolol, 172 (8) beats, rain-1 during atenolol, and 182 (10) b e a t s . m i n -1 during verapamil infusion (P < 0.001). Differences b e t w e e n the pairs of t r e a t m e n t s were also significant. Maximal p o w e r output (Wmax) was 212 ( 4 6 ) W during propranolol, 234 (51) W during atenolol and 224 (44) W during the verapamil infusion (P < 0.01). Pairwise c o m p a r i s o n s r e v e a l e d that only the difference b e t w e e n p r o p r a n o l o l and atenolol was significant. In the second study, the plasma concentrations of propranolol and verapamil were similar at rest, and that of atenolol was significantly lower ( P < 0.05). D u r i n g the 10 min exercise period the concentrations of verapamil and p r o p r a n o l o l increased significantly [propranolot f r o m 51.9 (12.5) n g . m l 1 (t = 0 min) to 59.6 (10.6) ng.m1-1 (t = 10 min), P < 0.01; verapamil f r o m 50.9 (15.2) ng. ml 1 (t = 0 min) to 70.1 (10.6) ng- m l - ~ (t = 10 mm, P < 0.001)].
549 80" 0----'-
E 60"
propranolN atenolN veraparnil
40' o
20" --ex---rec-
~ r e s t m 0
•
|
-40
•
~
-30
•
-20
i
i
i
-t0
0
10
•
i
•
20
3'0
(mln)
time,
Fig.2. Plasma concentrations of propranolol, atenolol, and verapamil at rest, during exercise (ex), and during recovery (rec) during continuous IV infusion of the drugs (mean _+SEM) 5-
o-.-¢~---'------o-~_
0,
~
-
-
-
-
,~ -
o
-
-
-
propranolol
'
atenolol
-
verapamil
o
m
E
-5'
e~
-10" ~ r e s t -15 -40
"
i
-30
•
~
-20
-ex---rec•
/
-10 time
!
!
0
10
•
l
t
20
30
(rain)
Fig.3. Changes in plasma volume at rest, during exercise (ex), and during recovery (rec) during continuous infusion of propranolol, antenolol, and verapamil. SEM is not shown, but varied between 0.5 and 2.2 %
No significant change in atenolol concentration was seen during the same time period (33.7 (3.0)ng.mt -I (t = 0 min) and 33.7 (2.7) ng.m1-1 (t = 10 min)) (Fig.2). During exercise there was a significant drop in plasma volume, on average of 8 to 10 %, which was similar after all three infusions. During the recovery period plasma volume was still lower than in the pre-exercise period (Fig. 3). If the plasma concentrations of the drugs were corrected for the changes in plasma volume, the plasma concentration of verapamil still showed a statistically significant increase during exercise [from 50.9 (15.2)ng-ml -t at t = 0 m i n to 64.6ng.ml ~ at t=10min] (P
©
Springer-Verlag 1.992
Exercise and the pharmacokinetics of propranolol, verapamil and atenolol M.A. van Baak, J. M. V. Mooij, and E M. Ho Schiffers Departments of Pharmacolegyand Internal Medicine,Universityof Limburg,Maastricht,The Netherlands Received:December4, 1991/Acceptedin revisedform:April 22, 1992
Summary. The volumes of distribution of the fl-adrenoceptor blocking agents propranolol and atenolol, and the calcium antagonist verapamil, during exercise have been investigated, Changes in the plasma concentrations of atenolol and propranolol during exhaustive exercise at 70 % of maximal aerobic power were compared after i week of oral treatment (propranolol 80 mg b.d. and atenolol 100 mg once daily) in 12 healthy volunteers. In a second study the effect of 10 min exercise at 50 % of maximal aerobic power on steady state plasma concentrations of propranolol, atenolol and verapamit was compared in 7 healthy subjects. The drugs were administered by a continuous intravenous infusion. The plasma concentration of atenolol was not changed by exercise in either study, but the plasma concentrations of propranolol and verapamil were significantly increased in both studies. However, after correction for changes in plasma volume during exercise, the plasma propranolol concentration was not significantly elevated in the second study. From the results it is concluded that exercise led to a reduction in the volume of distribution ofpropranolol during prolonged exercise (25 rain) at 70 % W .... which was not clearly demonstrable during 10 rain exercise at 50 % Wm,x. The volume of distribution of verapamil was reduced during 10 min exercise at 50 % W .... No change in the volume of distribution of atenolol during exercise could be shown. The changes in the volumes of distribution of propranolol and verapamil during exercise may contribute to preventing an increase in the half-life of these drugs in patients performing prolonged physical exercise. Key words: Propranolol, Atenolol, Verapamil; pharmacokinetics, exercise
Exercise influences a number of physiological factors that may affect the pharmacokinetics of drugs, including haemodynamics, metabolism, pH, temperature and gastro-intestinal function [Van Baak 1990]. A previous study showed that prolonged low intensity exercise significantly
reduced the half-life (tl/2) of the fl-adrenoceptor blocking agent propranolol [Arends et al. 1986]. On the other hand, the t~/2of the calcium antagonist verapamil was not significantly affected by prolonged moderate exercise [Mooij et al. 1986]. These findings were unexpected, since both drugs show flow-dependent extraction by the liver. In both studies liver blood flow, estimated by indocyanine green clearance, was significantly reduced during exercise. Thus an increase rather than a fall or a lack of change in tl/2 was expected. The fact that no increase in t~tzwas found might be explained by a concomitant reduction in the volume of distribution (V) during exercise. Hurwitz et al. (1983) showed that the plasma concentration of propranolot after oral administration was increased during exercise and suggested that V of propranolol might be reduced during exercise. The present study was done to investigate changes in the V of propranolol, atenolol and verapamil during exercise. Propranolol and verapamil are both lipophilic drugs, with high plasma protein binding and a high hepatic extraction ratio, while atenolol is hydrophilic, shows low plasma protein binding and is eliminated by the kidneys [Goodman et al. 1990].
Subjects and methods Two separate studieswere performed.In the firstthe drugswere administeredorally,and in the secondintravenously.
Subjects The firststudywas done 12healthy,male volunteers(age20 to 27 y); in the secondstudy7 healthyvolunteers(age20 to 23 y;3 m, 4 f) took part. The protocoI of the studies was approved by the Ethics Committee of the Universityof Limburg,and all subjectsgavetheir written informedconsentto it.
Protocol of the studies The first studywas peformedas part of a largerstudyof the effectsof ~-adrenoceptor blockers on endurance exercise performance.The subjects came to the laboratory three times. On the first occasion
548 350 E
0
250
propranolol atenolol
O o
150
~rest--
50 -40
~exercise~
[
I
-20
0
•
time
aI. 1987]. For atenolol the procedure was: after addition of 1N NaOH 200 gl and 250 ng procainamide, as internal standard, to 1 ml plasma, the plasma was extracted with 6ml dichloromethane:l-butanol (19:1). The organic phase was dried in a water bath under N2 and the residue dissolved in 100 gl eluent methanol:water:acetic acid:Bic B-7 (23:75:0.8:1.5). The solution was subjected to HPLC with a gBondapack C18 column (Waters Inc., The Netherlands). For fluorimetric detection the excitation wavelength was set at 222 nm and the emission filter at 320 nm. The interassay coefficient of variation of the procedure was 6.2 %.
rec
i
i
20
40
i
0
I
10
(mln)
Fig.l. Plasma concentrations of propranolot and atenolot at rest, during exercise, and during recovery (rec) after i week of oral administration (mean + SEM)
maximal aerobic power (W,,,~) on a cycle ergometer (Lode, Groningen, The Netherlands) was determined in an incremental exercise test done to exhaustion. Before the :next two visits, the subjects were given either propranolol (80 mg b. d.) or atenolol (100 mg) p. o. each for one week, in random order. The subjects took the last dose 1 h before coming to the laboratory. Treatment periods were separated by at least one drug-free week. On arrival in the laboratory catheters were inserted into forearm veins in each arm. A continuous infusion of saline (2.5 ml. rain ~)was started and was continued until the end of the recovery period. After 30 min at rest, the subject performed a submaximal endurance exercise test at 70 % Wm~ until exhaustion. Before and after the initial 30 min rest period (t = -30 and 0 rain), after l0 and 20 min of exercise (t = 10 and 20 min), at the moment of exhaustion, and after 3, 6 and 10 min of recovery, venous blood samples were obtained for determination of haematocrit haemoglobin concentration, and plasma drug concentration. In the second study all subjects came to the laboratory three times after an overnight fast. On each occasion the subjects were given an intravenous infusion: propranolol, atenolol or verapamil, in random order. There was an interval of at least I week between tests. After arrival in the laboratory venous catheters were inserted into forearm veins in each arm. A bolus injection of the drug (propranolo1195 gg. kg 1;verapami1225 gg. kg- 1;atenolo135 gg. kg a) was administered over 5 rain, followed by continuous infusion (propranotol 42 gg. min-1; verapamil 60 gg. min- ~; atenolol 5 gg- min- ~) until the end of the experiment. The doses of the bolus and the infusion were chosen to obtain steady-state plasma concentrations of the three drugs of approximately 50 ng.ml-L After 90 rain of the infusion, an incremental exercise test to exhaustion was performed on a cycle ergometer (Lode, Groningen, The Netherlands) to determine the maximal aerobic work capacity (Wm~). After further 60 rain at rest, the subject exercised for 10 min on the cycle ergometer at 50 % of Wmax, Venous blood samples for determination of the plasma concentrations of the drugs were obtained after 150,175 and 180 min of the infusion (t = -30,-15 and 0 min), and during the 1st, 3rd, 5th and 10th rain of exercise (t=l, 3, 5, 10min) and recovery ( t = l l , 13, 15, 20 min). Haematocrit and haemoglobin concentrations were also measured.
Methods Haemoglobin concentration was determined with the OSM2 haemoximeter (Radiometer, Copenhagen) and haematocrit by micro-centrifugation. From changes in haemoglobin and haematocrit, changes in plasma volume were calculated [Dill and Costill 1974]. Propranolol, verapamil and atenolol concentrations were determined by HPLC with fluorimetric detection. The methods for propranolol and verapamil have previously been described [Mooij et
Data analysis Data are presented as mean with (SD). Statistical analysis was performed by two-tailed Student t-tests for paired observations. In the second study analysis of variance with repeated measurements was used to analyze differences between the three drugs; post-hoc pairwise comparisons between drug treatments were performed by Scheffe's F-test. P < 0.05 was considered statistically significant.
Results
Plasma concentrations of p r o p r a n o l o l and atenolol in the first study are shown in Fig. 1. The plasma concentration of p r o p r a n o l o l did not Change significantly b e t w e e n t = - 3 0 min and t = 0 min (Fig. 1). Similar results were o b t a i n e d for the plasma atenolol concentration. D u r i n g exercise, however, the plasma concentration of propranolol rose significantly, f r o m 168 ( 1 1 3 ) n g - m l ~ to 202 (125) ng. m l - t at 20 rain exercise (P -- 0.01). I n contrast, the plasma c o n c e n t r a t i o n of atenolol did not change during exercise [265 ( l l 5 ) ng.m1-1 at t = 0 m i n and 270 (100) ng. m l - 1 at t = 20 mini (Fig. 1). Within the 10 min recovery period, the plasma p r o p r a n o l o l c o n c e n t r a t i o n had r e t u r n e d to the pre-exercise level. T h e plasma atenolol concentration, on the o t h e r hand, rose during the recovery period [from 267 (100) ng/ml at exhaustion to 292 (107) ng. ml 1at 6 min recovery, P = 0.01). T h e changes in the plasma v o l u m e during exercise were within 5 % after each drug. C o r r e c t i o n of the plasma concentration of the drug for the change in plasma volume did not yield significantly different results. T h e results of the incremental maximal exercise test in the s e c o n d study were: maximal heart rate was 144 (9) b e a t s . m i n - 1 during propranolol, 172 (8) beats, rain-1 during atenolol, and 182 (10) b e a t s . m i n -1 during verapamil infusion (P < 0.001). Differences b e t w e e n the pairs of t r e a t m e n t s were also significant. Maximal p o w e r output (Wmax) was 212 ( 4 6 ) W during propranolol, 234 (51) W during atenolol and 224 (44) W during the verapamil infusion (P < 0.01). Pairwise c o m p a r i s o n s r e v e a l e d that only the difference b e t w e e n p r o p r a n o l o l and atenolol was significant. In the second study, the plasma concentrations of propranolol and verapamil were similar at rest, and that of atenolol was significantly lower ( P < 0.05). D u r i n g the 10 min exercise period the concentrations of verapamil and p r o p r a n o l o l increased significantly [propranolot f r o m 51.9 (12.5) n g . m l 1 (t = 0 min) to 59.6 (10.6) ng.m1-1 (t = 10 min), P < 0.01; verapamil f r o m 50.9 (15.2) ng. ml 1 (t = 0 min) to 70.1 (10.6) ng- m l - ~ (t = 10 mm, P < 0.001)].
549 80" 0----'-
E 60"
propranolN atenolN veraparnil
40' o
20" --ex---rec-
~ r e s t m 0
•
|
-40
•
~
-30
•
-20
i
i
i
-t0
0
10
•
i
•
20
3'0
(mln)
time,
Fig.2. Plasma concentrations of propranolol, atenolol, and verapamil at rest, during exercise (ex), and during recovery (rec) during continuous IV infusion of the drugs (mean _+SEM) 5-
o-.-¢~---'------o-~_
0,
~
-
-
-
-
,~ -
o
-
-
-
propranolol
'
atenolol
-
verapamil
o
m
E
-5'
e~
-10" ~ r e s t -15 -40
"
i
-30
•
~
-20
-ex---rec•
/
-10 time
!
!
0
10
•
l
t
20
30
(rain)
Fig.3. Changes in plasma volume at rest, during exercise (ex), and during recovery (rec) during continuous infusion of propranolol, antenolol, and verapamil. SEM is not shown, but varied between 0.5 and 2.2 %
No significant change in atenolol concentration was seen during the same time period (33.7 (3.0)ng.mt -I (t = 0 min) and 33.7 (2.7) ng.m1-1 (t = 10 min)) (Fig.2). During exercise there was a significant drop in plasma volume, on average of 8 to 10 %, which was similar after all three infusions. During the recovery period plasma volume was still lower than in the pre-exercise period (Fig. 3). If the plasma concentrations of the drugs were corrected for the changes in plasma volume, the plasma concentration of verapamil still showed a statistically significant increase during exercise [from 50.9 (15.2)ng-ml -t at t = 0 m i n to 64.6ng.ml ~ at t=10min] (P
