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At least 19 recordsLinked to original sources
PubMed1979

Propranolol glucuronide cumulation during long-term propranolol therapy: a proposed storage mechanism for propranolol.

The comparative disposition of propranolol glucuronide (PG) and propranolol was determined in 35 patients with hypertension or coronary artery disease during initiation of propranolol therapy, during steady-state conditions, and after discontinuation of propranolol (dose range, 40 to 960 mg daily, every 6 hr). The 2.3-fold PG cumulation in plasma was identical to propranolol cumulation. PG plasma levels were about 4 times as high as propranolol levels over the whole dose range. Unexpectedly slow terminal elimination rate of propranolol (t1/2 approximately 16 to 24 hr) on discontinuation of propranolol appeared to be related to equally slow PG elimination. PG and propranolol could be detected in plasma and urine up to 3 to 5 days after propranolol discontinuation. The PG formed in man was deconjugated to propranolol in the dog after intravenous administration, suggesting that PG may serve as a storage pool for propranolol. Observations consistent with systemic and enteric deconjugation of PG, including enterohepatic recirculation, may, at least in part, explain the observed propranolol cumulation as well as the slow elimination of propranolol after its discontinuation. PG renal clearance (29 to 70 ml/min) and PG plasma levels were highly dependent on glomerular filtration rate, suggesting that PG may cumulate abnormally in patients with severe renal disease.

Adolescent↗
PubMed1978

Pathways of propranolol metabolism. Use of the stable isotope twin-ion GC-MS technique to examine the conversion of propranolol to propranolol-diol by 9000g rat liver supernatant.

The metabolic conversion of propranolol to propranolol-diol [1-(1-naphthyloxy)-2,3-propyleneglycol] by rat liver 9000g supernatant was demonstrated to proceed through the intermediate 3-naphthyloxy-2-hydroxypropionaldehyde. Using side chain deuterated propranolol-d5 as substrate, propranolol-diol-d4 was produced, indicating an obligatory aldehyde intermediate. Analysis of desisopropylpropranolol obtained in the same incubation showed no loss of deuterium indicating that the possibility of rapidly tautomerizing imine intermediate did not make a significant contribution in this metabolic conversion. Desisopropylpropranolol, added in small amounts to the incubation mixture is more rapidly converted to the propranolol-diol than is propranolol, indicating that the major pathway of conversion of propranolol to its diol metabolite is through the desisopropylpropranolol intermediate.

Animals↗
PubMed1975

Brain concentration of propranolol in relation to hypotensive effect in the rabbit with observations on brain propranolol levels in man.

Intracerebroventricular (ICV) injection of propranolol in the dog, cat and rabbit produces a significant fall in arterial pressure. In the following experiments, regional brain propranolol concentrations and changes in mean arterial pressure (MAP) have been measured in the rabbit after central and peripheral administration of the drug and the results compared to human brain/plasma levels. In the conscious rabbit, ICV injection of l-propranolol (500 mug) produced a prolonged fall in MAP, maximal at 105 minutes (16.8 plus or minus 5.9 mm Hg below base line). The regional brain propranolol concentrations after ICV injection of 14C-dl-propranolol (530 mug) were determined and the levels compared to those achieved following i.v. infusion of the unlabeled drug (1.0 and 2.0 mg/kg/hr). The propranolol concentrations in the hypothalamus, medulla pons and midbrain after i.v. infusion were similar to the propranolol content in these areas at 60 and 120 minutes after ICV injection. Intravenous infusion of propranolol also resulted in significant falls in MAP between 60 and 120 minutes. In control studies, infusions of d-propranolol (1.0, 2.0 and 4.0 mg/kg/hr), which is virtually devoid of beta adrenoceptor blocking activity, produced only slight reductions in MAP. Postmortem studies in patients treated with prolonged i.v. infusions of d-propranolol as part of the treatment of paraquat poisoning indicate that the brain/plasma concentration of propranolol in man is similar to that observed in the rabbit. Propranolol is therefore highly concentrated in human brain tissue and comparable brain levels in the rabbit result in a hypotensive response.

Adult↗
PubMed1978

The contribution of propranolol metabolites to the fluorometric assay of propranolol in human plasma.

1. Studies were undertaken to determine the fluorescent properties of several propranolol metabolites under the conditions of the fluorometric propranolol assay. Of the metabolites studied, propranolol glycol and N-desisopropylpropranolol had significant molar fluorescent coefficients relative to propranolol (72 and 79% respectively). N-desisopropylpropranolol was extracted with the same efficiency as propranolol (greater than 90%) wheras the glycol metabolite had only 34% extraction efficiency. Addition of each metabolite to samples of human plasma containing propranolol produced the predicted increase in fluorescent intensity. 2. Gas chromatographic analysis of plasma collected from 22 hypertensive patients chronically receiving oral propranolol revealed low concentrations of propranolol glycol and N-desisopropylpropranolol relative to propranolol. The results of these studies indicate that fluorescent metabolites of propranolol are not present in sufficient concentration to significantly interfere with the fluorometric assay of propranolol.

Chromatography, Gas↗
PubMed1992

Beta-blockers: propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol, manifest atherogenicity on in vitro, ex vivo and in vivo models. Elimination of propranolol atherogenic effects by papaverine.

The addition of the beta-blockers propranolol, metoprolol, atenolol, pindolol, alprenolol and timolol to a culture of peritoneal macrophages or smooth muscle cells induced an increase in the intracellular cholesterol content. Blood serum obtained from a rabbit after a peroral administration of beta-blockers also induced cholesterol accumulation. This property of drug or blood serum obtained after peroral administration is conventionally referred to as atherogenic potential or atherogenicity. Regular administration of propranolol during a 21-day period evoked stable atherogenicity of rabbit blood serum. This was accompanied by stimulation of manifestations of atherosclerosis in the aorta deendothelialized with a balloon catheter. Propranolol increased neointimal thickening, lipid accumulation, an increase in cell number and in the collagen content. In vitro, the combination of propranolol with papaverine eliminated the atherogenic effect of propranolol which manifested itself as stimulation of cholesterol accumulation in cultured cells. Simultaneous peroral administration of propranolol and papaverine prevented the appearance of serum atherogenicity. Papaverine eliminated neointimal thickening, an increase in cell number and in the lipid and collagen contents evoked by propranolol. Papaverine itself had no effect on these parameters. Thus, the atherogenicity of propranolol as well as capacity of papaverine to eliminate beta-blocker atherogenicity revealed in cell culture was confirmed in vivo. We hope that these results may be useful in the development of new drugs and optimization of antiatherosclerotic drug therapy.

Adrenergic beta-Antagonists↗
PubMed1979

Measurement of propranolol, 4-hydroxypropranolol and propranolol glycol in human plasma.

An HPLC method for the quantitative determination of propranolol, 4-hydroxypropranolol, and propranolol glycol in human plasma is described. The limits of sensitivity for the method were: 1 ng/ml propranolol; 5 ng/ml 4-hydroxypropranolol; and 1 ng/ml propranolol glycol. Data obtained from 6 healthy volunteers given a single 160 mg oral dose of propranolol revealed mean (+/- SEM) peak plasma levels of 31 +/- 10 ng/ml for 4-hydroxypropranolol and 9 +/- 2 ng/ml for propranolol glycol. These plasma levels were less than the peak concentrations recorded for propranolol (123 +/- 34 ng/ml. The rates of plasma decay of these two metabolites were greater than that observed for propranolol.

Chromatography, High Pressure Liquid↗
PubMed1978

Plasma propranolol levels in beagle dogs after administration of propranolol hemisuccinate ester.

The hemisuccinate ester of propranolol was administered to beagle dogs to test its applicability as a potential prodrug of propranolol. Following oral administration of propranolol hemisuccinate, plasma propranolol levels were eight times higher than after an equivalent dose of propranolol hydrochloride. The hemisuccinate was absorbed rapidly, with peak plasma levels observed at 0.5--1 hr. Following intravenous dosing, the disappearance half-life of the prodrug from the plasma was 0.5 hr while the propranolol half-life was 1.7 hr. This study demonstrated the potential usefulness of the prodrug approach when a highly metabolized drug such as propranolol is protected from first-pass elimination.

Animals↗
PubMed1979

Plasma concentrations of propranolol and 4-hydroxypropranolol during chronic oral propranolol therapy.

1 The plasma levels of propranolol and 4-hydroxypropranolol have been measured in 17 hypertensive patients receiving chronic oral therapy with propranolol. 2 The range of plasma propranolol concentrations was from 5.3 to 300 ng/ml, and that of 4-hydroxypropranolol was from 2.1 to 36.0 ng/ml. 3 The mean (+/- s.d.) plasma concentration ratio of 4-hydroxypropranolol to propranolol was 0.130 (+/- 0.005); however, a very wide range was observed with individual values ranging from 0.057 to 0.241. 4 A statistically significant correlation was observed between the plasma concentration of 4-hydroxypropranolol and that of propranolol. 5 Propranolol and 4-hydroxypropranolol plasma concentrations were each significantly, but poorly, correlated with daily propranolol dose. 6 The clinical significance of the results has been discussed.

Adult↗
PubMed1976

Quantitative determination of propranolol, propranolol glycol and N-desisopropylpropranolol in brain tissue by electron capture gas chromatography.

A method for the quantitative determination of propranolol and two of its active metabolites, 3-(alpha-naphthoxy)-1,2-propanediol (propranolol glycol) and N-des-isopropylpropranolol, in brain tissue of mice is described. Tissues are homogenized in perchloric acid-acetonitrile. Propranolol and its metabolites are isolated from the supernatant by solvent extraction and separated and detected as their trifluoroacetyl derivatives by electron capture gas chromatography. Chemical structures of the derivatives were confirmed by gas chromatography-mass spectrometry. The electron capture detector response of all three compounds is high, 0.7-2.0 X 10(-16) moles/sec. Brain levels of 10-250 ng/g can be detected of all three compounds with high specificity and good precision.

Animals↗
PubMed1979

Comparison of a once daily long-acting formulation of propranolol with conventional propranolol given twice daily in patients with mild to moderate hypertension.

The effect of conventional propranolol tablets given twice daily has been compared with an equivalent dosage of a long-acting formulation of propranolol ('Inderal' LA)p given once daily in twenty-nine patients with mild to moderate hypertension. The study lasted 10 weeks. There was no significant difference in clinical response to the two treatments which were equally effective and well tolerated. A once daily dosage schedule should greatly aid patient compliance.

Adult↗
PubMed1975

Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine, and diazoxide: the use of AH 5158 in the treatment of hypertension.

1. Intravenous administration of compound AH 5158, which possesses alpha- and beta-adrenergic receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.

Blood Pressure↗
PubMed1978

Propranolol in thyrotoxicosis. Cardiovascular changes during thyroidectomy in patients pre-treated with propranolol.

The cardiovascular changes during anaesthesia and thyroidectomy have been studied in seven thyrotoxic patients prepared with propranolol. The heart rate and cardiac rhythm remained very stable throughout surgery. A 20% increase in mean arterial pressure occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgical stimulation. A decrease in cardiac output, due to decreased stroke volume, occurred during surgery, reaching a maximum of 21% during ligation of the thyroid vessels and returning to pre-operative values by the end of surgery. The fall in cardiac output was accompanied by raised central venous pressure and raised total peripheral resistance.

Adult↗
PubMed1992

Enantioselective oral bioavailability of 0-isovaleryl propranolol as a potential prodrug of propranolol.

The enantioselective oral bioavailability of propranolol (PL) from 0-isovaleryl-PL was determined and compared with parent PL in beagle dogs. The bioavailability of the individual enantiomer from the prodrug increased about 2 fold. The AUC ratio between the S(-)- and R(+)-isomer posed at 0.89 which was statistically not different from that obtained after administration of PL alone. These features indicate that 0-isovaleryl-PL promises to be a potential prodrug of PL from the pharmacokinetic and pharmacodynamic point of view.

Administration, Oral↗