Different effects of exercise on plasma concentrations of nebivolol, bisoprolol and carvedilol

In-vitro studies have shown that beta-blockers are taken up into and released from adrenergic cells together with epinephrine and norepinephrine. Consequently, studies in humans revealed an increase in plasma concentrations of propranolol and atenolol, whereas those of carvedilol were not affected by physical exercise. However, nebivolol and bisoprolol never were investigated on this issue.

Ten healthy males received oral doses of 5 mg nebivolol, 5 mg bisoprolol, and 50 mg carvedilol daily for one week in a cross-over fashion. Exercise was performed at 3 hours following oral intake of the respective last drugs on the eighth day. Blood samples were taken at rest, during the last minute of exercise, and after 15 min of recovery.

At rest and during exercise, heart rates were as follows: Nebivolol, 57 +/- 7 and 137 +/- 11 beats/min; bisoprolol, 55 +/- 5 and 139 +/- 14 beats/min; carvedilol, 56 +/- 5 and 135 +/- 13 beats/min, with no significant differences between the drugs. Plasma concentrations were as follows: Nebivolol-rest 0.273 +/- 0.029 ng/ml, exercise 0.274 +/- 0.035 ng/ml, recovery 0.272 +/- 0.035 ng/ml (n.s.). Bisoprolol-rest 4.99 +/- 2.73 ng/ml, exercise 6.49 +/- 5.58 ng/ml, recovery 4.90 +/- 3.06 ng/ml ( p < 0.01). Carvedilol-rest 10.3 +/- 9.3 ng/ml, exercise 9.7 +/- 8.2 ng/ml, recovery 6.5 +/- 5.6 ng/ml ( p < 0.05).

Plasma concentrations of bisoprolol increased during exercise and returned to baseline during recovery, a behaviour which would have been predicted according to present knowledge. However, exercise had no effect on plasma concentrations of nebivolol and carvedilol, a finding that is in contrast to previous results with other beta-blockers such as propranolol and atenolol. We conclude that both nebivolol and carvedilol are not taken up into and released from adrenergic nerves during exercise, a feature that clearly distinguishes these drugs from other beta-blockers so far investigated.