Single oral doses of (+)-, (-)- and (+/-)-bufuralol were administered to a healthy volunteer to compare the disposition and metabolism of the individual isomers and the racemate. Plasma levels and area under plasma curve (AUC) of the active isomer, (-)-bufuralol, were higher than those of the (+)-isomer; plasma clearance was correspondingly lower. Intermediate values were found for the racemate. The elimination half-life of (-)-bufuralol was shorter than that of (+)-bufuralol, but similar to the racemate. Both isomers were cleared almost entirely by metabolism. The main metabolic pathway for (-)-bufuralol was aromatic hydroxylation, whereas the principal route for (+)-bufuralol was conjugation. Phenol metabolites in the systemic circulation were present mainly as conjugates. Both isomers also underwent aliphatic hydroxylation. This pathway was more favoured by the (+)-isomer, although plasma levels and AUC of the principal product, 2'-hydroxy-bufuralol, were almost identical for the two forms. Major differences in metabolic fate thus had relatively little effect on the disposition of pharmacologically active metabolites.
A sensitive method for the simulataneous determination of bufuralol and its pharmacologically active metabolites in huamn plasma is described. The O-timethylsilyl,N-trifluoroacetyl derivatives are assayed by mass fragmentography. Sensitivity is 1 ng 76(-1) plasma for bufaralol and about 250 pg ml(-1) for the metabolites. An alternative procedure which uses gas chromatography with electron capture detection is also described. The sensitivity of this is about 10 ng ml(-1) plasma for all drug-related components.
The metabolism of a new~-adrenoceptor blocking agent, bufuralol, 7-ethyl-iX[(tertiary butylamino)-methylj-2-benzofuran methanol. HCI, was studied in rat, dog and man. After oral administration of the labelled drug, 34 % of dose was eliminated in urine by the rat, 50 % by the dog, and 75 %by man. Examination of urine extracts by gas chromatographymass spectrometry with single-and multiple-ion monitoring indicated the presence of twelve metabolites. These were identified as mono-, di-and tri-oxygenated analogues of the parent drug. They had been formed from four main pathways, two involving aliphatic and two aromatic hydroxylation. All but one were present partly in conjugated and partly in free form. Three further metabolites were detected in dog urine. Two were conjugates with an unidentified hexuronic acid moiety, the third the hydroxy-acid resulting from degradation of the~-hydroxyamine side-chain of the parent drug.
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.
1. The metabolic fate of the substituted cinnamic acid ester, Ro 03-6037, has been examined in rat, mouse, baboon, dog, marmoset, rabbit and man. 2. All species are capable of reducing the cinnamate double bond, but the subsequent one-carbon fragment loss can be carried out only by rat, dog, rabbit and marmoset. 3. The inability of man, as well as baboon and mouse, to perform this terminal metabolic step, which results in formation of the active anti-inflammatory agent, renders the compound unsuitable as a drug for humans. 4. Reduction of the double bond is not carried out by gut flora. 5. An h.p.l.c. analytical method is described for estimation of the metabolites in biological fluids.
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