Relationship between plasma concentrations and cardiac beta‐ adrenoceptor blockade‐a study with oral and intravenous bopindolol.

Abstract

1 Bopindolol, an esterified P-adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio-receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. 2 After intravenous administration the half-life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one-compartment model occurred with a half-life of about 4 h. There were indications for a longer ,B phase of elimination with a half-life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%.3 Cardiac P-adrenoceptor,blockade was determined as the reduction in exerciseinduced tachycardia. With oral doses the maximum effect was reached after 3 h (-29 beats min-' after 1 mg, -40 beats min--after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (-33 beats min-1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present. 4 A good linear correlation between the logarithm of plasma concentration and the reduction of exercise-induced tachycardia was obtained from data measured after the maximal effect had been reached. At earlier time points (i.e. before the maximal effect was reached) plasma concentrations coincided with a smaller reduction of exerciseinduced tachycardia than was achieved with identical plasma concentrations at later time points. This observation is compatible with the hypothesis that the cardiac P-adrenoceptors lie outside the plasma compartment.

Pharmacological experiments in healthy volunteers with bopindolol, a long‐acting beta‐adrenoceptor blocking drug with partial agonist activity.

“…This supports the hypothesis of a metabolic transformation of the parent compound into the active drug, hydrolysed bopindolol, in the body. In a pharmaco- kinetic study a relatively long invasion half life of the active compound was found (Aellig et al, 1985). In the same study it was found also that even after intravenous drug administration the maximum plasma concentration of the active metabolite is reached only about 2 h after the injection.…”

“…This is Following oral administration the onset of action of equipotent B-adrenoceptor blocking doses of bopindolol is slower than that of pindolol or other ,-adrenoceptor blocking drugs. Furthermore, in studies in which the drug was administered intravenously (Aellig et al, 1985) despite the fact that a marked effect was observed within 30 min, the maximum effect was not attained until 3 h after injection. This supports the hypothesis of a metabolic transformation of the parent compound into the active drug, hydrolysed bopindolol, in the body.…”

Bopindolol: A Slowly Dissociating Antagonist from the β-Adrenoceptors in Guinea Pig Atria

“…Several previous reports have indicated (1) the slowly reversible nature of binding of bopindolol to receptors [10]; (2) the presence of active metabolites [11]; (3) the shallow slope of the plasma concentration-effect relationship [12,13], and (4) the small dissociation Hosohata/Hattori/Shen/Okuyama/ Kaneko/Ohnuki/Suzuki/Nagatomo constant of the drug-receptor complex [14]. Our previous study [2] also showed a slow dissociation of bopindolol and metabolite 18-502 from ß-ARs in the rat and guinea pig heart using pharmacological methods and the radioligand-binding assay.…”

“…There is increasing evidence that bopindolol possesses long-acting ß-blocking action with high affinity and partial agonist activity to the ß-ARs in both healthy volunteers and animal models [9,11,13,14], suggesting that less frequent administration may be necessary than with most other ß-blockers [6,7,11]. It is well known that one active metabolite (18-502) also has strong ß-blocking action, suggesting that this metabolite also contributes to the long-lasting effects of bopindolol [2].…”

Sustaining Effects of Bopindolol on Inhibitory Chronotropic Actions in Guinea Pig Atria

“…Several hypotheses have been reported to explain the dissociating and/or residual inhibitory effects of bipindolol from ß-ARs in heart muscles; i.e. (1) the slowly reversible nature of binding of bopindolol from receptors [11]; (2) the presence of active metabolites [12]; (3) the shallow slope of the plasma concentration-effect relationship [13,14], and (4) small dissociation constant of the drug-receptor complex [15]. Our previous study [6] also showed slow dissociation of bopindolol and 18-502 from ß-ARs in the rat and guinea pig heart using pharmacological and the radioligand binding assay methods.…”