Pharmacodynamic and pharmacokinetic studies on bufuralol in man.

Abstract

1 Observations were made in eight subjects who exercised before and at 1, 2, 4, 6, 8 and 24 h after the double-blind oral administration of placebo, bufuralol 7.5, 15, 30, 60 and 120 mg and propranolol 40 and 160 mg. 2 The exercise heart rate remained constant after placebo. Bufuralol 7.5 mg and propranolol 40 mg reduced exercise heart rate up to 6 and 8 h respectively after dosing but bufuralol 15, 30, 60 and 120 mg and propranolol 160 mg were still active at 24 h. 3 The lowest exercise heart rate occurred at 2 h after all active treatments. Bufuralol 60 and 120 mg produced similar reduction in exercise tachycardia as propranolol 40 mg but less than propranolol 160 mg. 4 Plasma levels of bufuralol and its two major metabolites were measured. The peak plasma concentrations of bufuralol occurred at 1.5 h after 7.5 mg and at 2 h after the other doses of bufuralol. In six subjects the plasma elimination half-life of bufuralol was 2.61 + 0.18 h and in the other three subjects 4.85 ± 0.35 h. There was a corresponding longer time to peak concentration and plasma elimination half-life of the two metabolites in these three subjects. 5 These findings show that bufuralol is a potent ,B-adrenoceptor antagonist with partial agonist activity. It has a long duration of action and there is bimodal metabolism of the drug in man.

Survey of Pharmacological Activity and Pharmacokinetics of Selected β-Adrenergic Blockers in Regard to Their Stereochemistry

“…In the group of heterocyclic analogues marked activity was exhibited by bufuranol, 2-(2-methylpropan-2-ylamino)-1-(7-ethyl-1-benzofuran-2-yl)ethanol, a non-selective β-blocker with intrinsic sympathomimetic effects. Higher activity was found in its (R)-(-)-isomer [39][40][41][42].…”

Soft Drugs. 12. Design, Synthesis, and Evaluation of Soft Bufuralol Analogues

“…For example, bufuralol l2,13 (Figure ) is a potent, nonselective β-blocker − that has proven to be very effective in lowering blood pressure and heart rate. It undergoes a complex series of metabolic transformations in humans to alcohol and ketone metabolites that also possess significant β-receptor-blocking activities while having longer half-lives. − The oxidative transformation of bufuralol by the hepatic cytochrome P450 isozymes is under genetic control and falls under the debrisoquine/spartein phenotype. − A genetically determined defect of the hydroxylation occurs in up to 10% of the Caucasian population (poor metabolizers) . This situation can further complicate the pharmacokinetic profile by increasing drug bioavailability and prolonging the elimination half-life so as to produce more intense and sustained β-blockade − that, in turn, can lead to severe hypotension and bradycardia …”

“…It undergoes a complex series of metabolic transformations in humans to alcohol and ketone metabolites that also possess significant β-receptorblocking activities while having longer half-lives. [17][18][19][20][21][22] The oxidative transformation of bufuralol by the hepatic cytochrome P450 isozymes is under genetic control and falls under the debrisoquine/spartein phenotype. [23][24][25][26] A genetically determined defect of the hydroxylation occurs in up to 10% of the Caucasian population (poor metabolizers).…”