Relationship between pharmacokinetic and pharmacodynamic behaviour of bufuralol and its metabolite Ro 3-7410 in hypertensive patients

Eckert, M.; Cocco, Giuseppe; Strozzi, C; Heizmann, P.; Sfrisi, C.

doi:10.1007/bf00609890

Cited by 7 publications

(4 citation statements)

References 3 publications

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“…42 To support this assumption complete and rapid intestinal absorption of BUF and DBQ were observed in mammals and experimental data showed a high passive permeability of BUF in monolayer cells. [43][44][45] All of these observations are in line with our assumption of rapid passive diffusion process in rat liver cells.…”

Section: Partition Coefficient and Fraction Unboundsupporting

confidence: 74%

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

Haddad

Poulin²,

Funk

2010

Journal of Pharmaceutical Sciences

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Section: Partition Coefficient and Fraction Unboundsupporting

confidence: 74%

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

Haddad

Poulin²,

Funk

2010

Journal of Pharmaceutical Sciences

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“…The correlation of the percent reduction of exercise heart rate and the logarithm of the plasma concentration of the parent drug was better for the parent drug than for the parent drug plus metabolites, which suggests that the P-adrenoceptor blocking effect of bufuralol results from the action of the parent drug rather than from the metabolites. This conclusion is different to that of other investigators (George et al, 1975;Tschopp et al, 1978;Eckert et al, 1983).…”

Section: Discussioncontrasting

confidence: 92%

Pharmacodynamic and pharmacokinetic studies on bufuralol in man.

Pringle¹,

Francis²,

East³

et al. 1986

Brit J Clinical Pharma

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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.

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“…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 …”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2000

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In the search for more potent but still short-acting beta-blockers (BB), the methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, 2-(1-adamantyl)ethyl, and methylthiomethyl esters of the acidic inactive metabolite of bufuralol were synthesized based on the "inactive metabolite" approach. The cleavage of the ester bond by blood and tissue esterases rapidly deactivates these compounds, resulting in an ultrashort duration of action. The beta-antagonist potencies and time courses of actions of the new "soft" BBs were characterized by recording ECG and intra-arterial blood pressure (BP) in rats. In the isoproterenol-induced tachycardia model, while bufuralol at an iv dose of 1 mg/kg (3.8 micromol/kg) diminished heart rate (HR) for at least 2 h, the effects of the soft drugs lasted for only 10-30 min at equimolar dose. The inactive metabolite did not decrease HR significantly. The first four members of this series of compounds showed the highest beta-blocking potencies, ranging between 25% and 50% of that of bufuralol. Next, the effects of these most active compounds on resting HR and BP were evaluated in comparison to esmolol. Infused for 10 min at a rate of 20 micromol/kg/min, esmolol decreased HR and mean arterial pressure (MAP) by 40% and 60%, respectively. The soft drugs at doses ranging only between 2 and 4 micromol/kg/min resulted in a 20-40% decrease in HR and a 30-50% reduction in MAP. However, the time courses of both the bradycardic and hypotensive effects of the soft drugs were superimposable to that of esmolol, diminishing within 60 min after the discontinuation of the infusions.

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Relationship between pharmacokinetic and pharmacodynamic behaviour of bufuralol and its metabolite Ro 3-7410 in hypertensive patients

Cited by 7 publications

References 3 publications

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

Extrapolating In vitro Metabolic Interactions to Isolated Perfused Liver: Predictions of Metabolic Interactions between R-Bufuralol, Bunitrolol, and Debrisoquine

Pharmacodynamic and pharmacokinetic studies on bufuralol in man.

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

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