The basic pharmacokinetics of bisoprolol were investigated in three independent studies involving 23 healthy volunteers. After administering 20 mg of 14C-bisoprolol orally, mean elimination half-lives of 11 hours for the unchanged drug and 12 hours for total radioactivity were observed. The enteral absorption of bisoprolol was nearly complete. Fifty percent of the dose was eliminated renally as unchanged bisoprolol and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral and intravenous administration of 10 mg bisoprolol to 12 subjects yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 L/hr and 9.6 L/hr, respectively. The volume of distribution was 226 L. Concomitant food intake did not influence the bioavailability of bisoprolol.

The pharmacokinetics of bisoprolol were investigated following oral administration of 10mg once daily for 7 days in 8 healthy subjects, in 14 patients with different degrees of renal impairment and in 18 patients with liver disease. In healthy subjects peak and trough steady-state concentrations of 52 micrograms/L and 11 micrograms/L, respectively, an elimination half-life of 10.0 hours and total body clearance of 14.2 L/h were observed. 5.21 mg/24 hours of unchanged bisoprolol were recovered following urinary excretion during the dosage interval. In 11 patients with renal impairment (mean CLCR = 28 +/- 5 ml/min/1.72m2) half-life was prolonged to 18.5 hours, and peak and trough concentrations were 74 and 32 micrograms/L, respectively. Correspondingly, urinary excretion decreased to 3.35 mg/24 hours and total body clearance to 7.8 L/h. In uraemic patients (CLCR less than 5 ml/min/1.73m2) the total clearance of bisoprolol was 5.0 L/h and the elimination half-life was 24.2 hours. In patients with liver cirrhosis half-life increased to 13.5 hours, steady-state peak and trough concentrations increased to 62 and 22 micrograms/L, respectively, and total body clearance decreased to 10.8 L/h. The present study indicates that in patients with impairment of kidney or liver function accumulation of bisoprolol above a factor of 2 did not occur. However, in the terminal stages of insufficiency of kidney or liver function bisoprolol dosage should not exceed 10mg.

In 6 healthy volunteers the pharmacokinetics of bisoprolol under steady-state conditions was investigated over three consecutive phases: over 7 days of 10 mg of bisoprolol once daily per os, 7 days of 10 mg of bisoprolol once daily plus 400 mg of cimetidine t.i.d. and 14 days of 10 mg of bisoprolol and 600 mg of rifampicin once daily with adequate intervals free of medication. After therapy with bisoprolol alone peak plasma levels (Cssmax) of the beta-blocker were 55.5 +/- 6.4 ng/ml (means +/- SEM), area under the plasma level-time curve (AUC tau) was 597 +/- 70 ng/ml.h, total body clearance (CL) 15.8 +/- 1.8 l/h and elimination half-lives (t1/2 beta) 10.1 +/- 1.2 h. Cimetidine did not cause any significant changes in the pharmacokinetics of bisoprolol. Co-administration of rifampicin resulted in a decrease in Cssmax (43.0 +/- 6.9 ng/ml), AUC tau (397 +/- 54 ng/ml X h) and t1/2 beta (6.2 +/- 0.4 h). Accordingly, total body clearance increased to 23.8 +/- 2.5 l/h (p less than 0.05). In conclusion bisoprolol showed a statistically significant but probably clinically not important interaction with the enzyme-inducing drug rifampicin, but not with the enzyme inhibitor cimetidine.

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The pharmacodynamic profile of bisoprolol, a new beta 1‐selective adrenoceptor antagonist, was investigated in four independent studies including 36 healthy male volunteers. Using the model of exercise‐ induced tachycardia (ET) the beta‐adrenoceptor blocking properties of bisoprolol (2.5‐40 mg) were examined in comparison to metoprolol (50 and 100 mg), propranolol (40 and 80 mg) and atenolol (50 and 100 mg). The maximal reduction of ET was achieved between 1 and 4 h following single oral administration. The dose‐response relationship using individual maximal reduction of ET showed, on a molar basis, that bisoprolol is about 5, 7 and 10 times more effective than propranolol, atenolol and metoprolol, respectively. In the model of insulin‐induced hypoglycaemia bisoprolol behaved as a beta 1‐selective adrenoceptor antagonist. There was a good correlation (r = 0.94) between the log bisoprolol concentration and the reduction in exercise‐induced tachycardia. Bisoprolol is a potent new cardioselective beta‐ adrenoceptor antagonist with a competitive action at beta 1‐ adrenoceptors.