RESUMEN
Hepatic drug metabolism influenced by genetic and environmental factors is a major source of variation in the response to a number of beta-adrenoceptor antagonists. The first study described here was carried out to define the role of a genetic determinant (debrisoquine-type oxidation polymorphism) on plasma concentration of bopindolol and its pharmacological effect. Atenolol was used as a negative and metoprolol as a positive control. In a second study, the relative potency and duration of action of bopindolol were assessed in comparison to atenolol and slow-release oxprenolol. The first study was carried out using 10 healthy volunteers (6 extensive and 4 poor metabolizers), and the second study was carried out using 12 volunteers, all of whom were extensive metabolizers. Genetic polymorphism did not influence the kinetic behavior or pharmacological effects of atenolol. The elimination of bopindolol was slightly but significantly prolonged in poor metabolizers, but this did not significantly alter the cardiac effects of the drug. In the case of metoprolol poor metabolizers showed a significant prolongation of drug elimination, and this was associated with a significant prolongation of the cardiac effects of the drug. The second study revealed that, in terms of cardiac beta-adrenoceptor blockade, 1 mg bopindolol was equipotent to 100 mg atenolol or 160 mg slow-release oxprenolol and that both bopindolol and atenolol had a longer duration of action than slow-release oxprenolol. It is concluded that bopindolol is a potent beta-adrenoceptor antagonist with a very long duration of action which shows little interindividual variability.
Asunto(s)
Antagonistas Adrenérgicos beta/metabolismo , Pindolol/análogos & derivados , Antagonistas Adrenérgicos beta/sangre , Antagonistas Adrenérgicos beta/farmacología , Adulto , Humanos , Oxidación-Reducción , Pindolol/sangre , Pindolol/metabolismo , Pindolol/farmacología , Polimorfismo GenéticoRESUMEN
Ten healthy subjects whose genetic oxidative phenotype had been determined (6 extensive and 4 poor metabolizers of the debrisoquine-sparteine type of polymorphism) received single oral doses of 3 beta-blockers: atenolol, bopindolol and metoprolol. The plasma concentrations and the extent of the decrease in exercise-induced tachycardia were determined. The oxidative polymorphism was only significant for substances that had a high hepatic first pass metabolism, such as metoprolol. The metabolic pathway under genetic control was highly stereoselective. This observation must be taken into account when assessing the relation between the plasma concentration and effect of these drugs, which are often administered as racemic mixtures.
Asunto(s)
Antagonistas Adrenérgicos beta/sangre , Atenolol/sangre , Metoprolol/sangre , Pindolol/análogos & derivados , Antagonistas Adrenérgicos beta/farmacología , Adulto , Atenolol/farmacología , Humanos , Individualidad , Metoprolol/farmacología , Oxidación-Reducción , Pindolol/sangre , Pindolol/farmacología , Polimorfismo GenéticoRESUMEN
The beta-blocking agent bufuralol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (1'-hydroxy-bufuralol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behavior of the parent compound and three of its metabolites was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Bufuralol was given orally to all subjects (20 mg); some of the healthy volunteers also received the drug intravenously (5 mg). Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its halflife of elimination was not markedly influenced. The behavior of 1'-hydroxy-bufuralol was consistent with a decreased renal clearance. The behavior of bufuralol in patients with renal failure was analyzed using the clearance approach. From this analysis it appears that the presystemic biotransformation of bufuralol is decreased in renal failure and that changes in systemic clearance are compensated in our patients by modifications of the volume of distribution, resulting in little net change in the halflife of elimination.
Asunto(s)
Antagonistas Adrenérgicos beta/metabolismo , Etanolaminas/metabolismo , Enfermedades Renales/metabolismo , Hígado/metabolismo , Adulto , Anciano , Femenino , Humanos , Riñón/metabolismo , Cinética , Masculino , Matemática , Tasa de Depuración Metabólica , Persona de Mediana EdadRESUMEN
Tolamolol is subject to first-pass metabolism and is eliminated from the body almost entirely by biotransformation. Its major metabolite in plasma (4-hydroxy-tolamolol) is biologically active and may contribute to the pharmacological effect of the drug. The effect of renal failure on the behaviour of the parent compound and of its metabolite was studied by comparing their kinetics in normal volunteers and in patients with severe renal insufficiency. Tolamolol was given orally to all subjects at a 100 mg dose. Renal failure was found to be associated with a marked increase of the areas under the plasma concentration-time curves of the parent compound, whereas its half-life of elimination was not markedly influenced. The behaviour of tolamolol in patients with renal failure was analysed using the clearance approach. From this analysis it appears that the presystemic biotransformation of tolamolol is decreased in renal failure.