benzofurans and benzarone

Benzbromarone is one of the main uricosuric drugs currently used. We determined plasma concentrations of benzbromarone, bromobenzarone, and benzarone and 24 hour uric acid excretion in ten healthy individuals following fasting application of two different non-micronised benzbromarone brands. In addition we explored the influence of adjusting urinary pH to near neutral values and of concomitant food intake. Benzbromarone was more rapidly absorbed from the test preparation than from the reference preparation; the extent of systemic availability did not differ significantly. Urinary pH adjustment had no clearcut effect, whereas food intake retarded drug absorption (even though not significant because of the variability of the data). Binding of benzbromarone to plasma proteins exceeded 99%. Bromobenzarone and benzarone were not detectable and are unlikely to be major metabolites of benzbromarone. Instead we found two other compounds suggestive of metabolites, one of them being monohydroxilated benzbromarone. The plasma concentrations of the parent compound in one subject exceeded those of the rest of the group, possibly indicating genetic differences in drug metabolism. The uricosuric effect was not related to benzbromarone plasma concentrations.

Topics: Adult; Benzbromarone; Benzofurans; Humans; Hydroxylation; Inactivation, Metabolic; Male; Protein Binding; Purines; Uric Acid

Topics: Benzbromarone; Benzofurans; Chronic Disease; Clinical Trials as Topic; Edema; Female; Fibrinolytic Agents; Humans; Leg; Male; Venous Insufficiency

Topics: Adult; Aged; Benzbromarone; Benzofurans; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Premedication; Thrombosis; Varicose Veins

Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.

Topics: Amiodarone; Animals; Apoptosis; Benzbromarone; Benzofurans; Cell Line, Tumor; Hepatocytes; Ketone Bodies; Liver; Male; Membrane Potentials; Mitochondria, Liver; Mitochondrial Swelling; Molecular Structure; Necrosis; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Benzofuran derivatives: amiodarone, benziodarone, benzbromarone and benzarone, extracted from plasma, were separated by TLC method on silica gel by ascending and horizontal developments, using suitable mobile phases. The substances were identified by reaction with potassium permanganate solution, either by Dragendorff (modified after Amelink) or Sonnenschein reagents (up to the amounts of 250 ng of amiodarone and benzarone and 500 ng of benziodarone and benzbromarone).

Topics: Amiodarone; Benzbromarone; Benzofurans; Chromatography, Thin Layer; Fibrinolytic Agents; Humans; Uricosuric Agents; Vasodilator Agents

We report a case of chronic active hepatitis caused by benzarone, a benzofuran derivative used in Europe for the treatment of peripheral venous disorders. Jaundice and serum alanine aminotransferase activity increased while drug administration was continued, but promptly decreased when it was eventually interrupted. Liver lesions were those of chronic active hepatitis. Anti-smooth muscle antibodies were present at a titer of 1:500 and disappeared 8 months after withdrawal of benzarone.

Topics: Alanine Transaminase; Benzbromarone; Benzofurans; Chemical and Drug Induced Liver Injury, Chronic; Female; Fibrinolytic Agents; Hepatitis, Chronic; Humans; Middle Aged

1. The metabolic fate of 14C-benzarone in the rat and dog has been compared to that in human subjects. An oral dose was well-absorbed in all three species. However, the 14C excretion patterns differed: humans (100 mg) excreted means of 73 and 19% dose in the urine and faeces respectively, whereas the rat (2 mg/kg) and dog (0.5 mg/kg) excreted greater than 80% in the faeces, mostly during the first 48 h. 2. Much of the faecal 14C was attributable to 14C excreted in the bile which amounted to 59% in the 7 h bile collected from an intravenously dosed dog, and a mean of 72% in the 24 h bile of orally dosed rats. Enterohepatic circulation of 14C was demonstrated in rats. 3. Total 14C in human plasma reached peak concentrations between 1-2 h and declined relatively rapidly, to about 10% of this value within 24 h. Unchanged benzarone was not detected in plasma (less than 25 ng/ml), even after a 400 mg dose, but conjugated benzarone was--accounting for about 10% of the peak concentration of 14C. In the dog, by contrast, conjugated benzarone accounted for about 50% of the peak concentration of 14C of 0.96 microgram equiv./ml at 1 h. The extent of binding of benzarone to human plasma proteins (greater than 99%; in vitro was slightly greater than that (greater than 96%) of total 14C (ex vivo, representing metabolites). 4. Examination of metabolite profiles by h.p.l.c. suggested that in the rat and dog, at least 70% absorbed dose was eliminated by direct conjugation, whereas in humans at least 70% was hydroxylated before conjugation, mainly with glucuronic acid. Hydroxylation occurred in the benzofuran ring and/or the ethyl side-chain. The principal urinary metabolite in humans was the conjugate(s) of the 1-hydroxylated ethyl side-chain derivative (mean 26% dose).

Topics: Adult; Animals; Benzbromarone; Benzofurans; Bile; Biotransformation; Blood Proteins; Chromatography, High Pressure Liquid; Dogs; Feces; Fibrinolytic Agents; Humans; Intestinal Absorption; Kinetics; Male; Mass Spectrometry; Rats; Rats, Inbred Strains; Species Specificity

Benzarone (the debrominated metabolite of the uricosuric drug benzbromarone) has been proposed for treatment of vascular disorders. An assay was developed for the quantitation of total benzarone (conjugated and unconjugated) in plasma and urine, following oral intake of benzarone. Enzymatic hydrolysis of the samples with beta-glucuronidase/arylsulphatase, extraction, gradient elution high-performance liquid chromatography with reversed-phase columns and UV detection were used for the assay. The concentration ranges, precision and sensitivities were: 0.01-2 micrograms/ml, 3-5% and 0.01 microgram/ml, respectively, for both plasma and urine. These results were validated by gas chromatography-mass spectrometry after methylated derivatives were prepared. Enzymatic hydrolysis of plasma with pure beta-glucuronidase or arylsulphatase showed that the relative amounts of unconjugated, glucuronidated, and sulphated benzarone were 6, 12 and 82% respectively, for both plasma and urine.

Topics: Adult; Arylsulfatases; Benzbromarone; Benzofurans; Biotransformation; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Glucuronidase; Humans; Indicators and Reagents; Male

Topics: Benzbromarone; Benzofurans; Chemical Phenomena; Chemistry; Dermatitis, Contact; Female; Humans; Middle Aged

Using 2-ethyl-3-(4- hydroxybenzoyl )benzofuran ( EHBB ) as an example, biotransformation in rabbits and rats and by rat hepatocyte suspensions was studied by high-performance liquid chromatography (HPLC) and mass spectrometry. The biotransformation of N-alkyl-substituted piperidines by rat hepatocytes gives valuable information about the pharmacodynamics of this series of compounds. It is demonstrated that a simple reversed-phase HPLC pre-column technique is much superior to the classical sample purification via extraction. The utility of hepatocytes for the investigation of drug metabolism is demonstrated.

Topics: Animals; Benzbromarone; Benzofurans; Bile; Biotransformation; Body Fluids; Chromatography, High Pressure Liquid; Humans; In Vitro Techniques; Liver; Male; Mass Spectrometry; Pharmaceutical Preparations; Piperidines; Rabbits; Rats; Species Specificity

The influence of 2-ethyl-3-(4-hydroxy-benzoyl)-benzofurane (benzarone, Fragivic) on the energy metabolism of the wall of the rabbit common carotid artery and the rat portal vein was investigated by measuring the oxygen consumption of in vitro incubated vessel segments. Benzarone increased the oxygen consumption of the carotid artery either in whole vessel wall segments or in intima-media preparations. The increase was concentration-dependent. The basal tone of the artery did not change during incubation. Benzarone decreased the oxygen consumption of the portal vein, while spontaneous phasic activity was blocked and the basal tone lowered. The results suggest that, besides its antagonistic effects on mediators of muscle contraction, benzarone influences the metabolism of the smooth muscle cells directly. An uncoupling effect on the oxidative phosphorylation, which would be consistent with the antiinflammatory properties of benzarone, is discussed.

Topics: Animals; Benzbromarone; Benzofurans; Carotid Arteries; Female; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Oxidative Phosphorylation; Oxygen Consumption; Portal Vein; Rabbits; Rats; Rats, Inbred Strains; Uncoupling Agents

Topics: Benzbromarone; Benzofurans; Fibrinolytic Agents; Humans; Intermittent Claudication; Muscles; Oxygen Consumption

Topics: Animals; Benzbromarone; Benzofurans; Binding Sites; Cyclic AMP; Cyclic GMP; Fibroblasts; Humans; In Vitro Techniques; Platelet Aggregation; Rats; Trout

Rats of BD X strain and SHR/NIH Montreal Ingelheim strain (genetic hypertension) received a diet containing 3.9% cholesterol or 3.7% cholesterol plus 0.6% benzarone, respectively, and libitum for 5 or 9 months. The following chemical and ultrastructural results were obtained. 1. The cholesterol-benzarone diet causes a body weight reduction of 10%, a relative increase of serum HDL and a corresponding decrease of serum LDL and VLDL, as compared with the effects of the cholesterol diet. No differences of total serum cholesterol and serum triglycerides between the two groups were observed. 2. The aorta of cholesterol fed animals shows a slight but statistically not significant increase of total cholesterol content. 3. No differences in the composition of connective tissue components (collagen, elastin, uronic acid content) between the cholesterol fed animals and a control group on normal diet could be detected. 4. Electron micrographs of several vessel wall areas from cholesterol fed hypertensive animals revealed fibrosis, necrosis of media muscle cells and an increase of matrix vesicles. Severe damages were found in coronary arteries and in the caudal arteries. 5. Cholesterol feeding of hypertensive rats increases the cholesterol content of liver 10fold and the triglycerides content 3fold as compared with liver lipids of control rats. Benzarone application to cholesterol fed rats effects a statistically significant decrease of liver cholesterol and triglycerides.

Topics: Animals; Arteries; Benzbromarone; Benzofurans; Blood Pressure; Body Weight; Cholesterol, Dietary; Fibrinolytic Agents; Lipid Metabolism; Lipids; Male; Rats

Local transmural electrical stimulation by chronically implanted electrodes of a carotid artery in rabbits was daily repeated. The area in direct contact to the electrodes covered 0.5 x 5 mm of adventitia. The carotid walls received DC impulses (10 ms/imp, 10 Hz, 100 microA) 2 x 1/2 h daily. Within 4 weeks a proliferate of smooth muscle cells develops in the intima at the spot where the anode contacts the outside of the artery. If the animals were fed 2% cholesterol in normal food the proliferate developed to a typical atheroma. The other parts of the arterial system did not develop plaques within this time. At the luminal side of the plaques no significant adhesions of platelets could be seen. Addition of 300 mg 2-ethyl-3-[-4-hydroxybenzoyl]-benzofuran (benzarone, Fragivix) to 100 g of animal food (containing 2% cholesterol) caused a less pronounced increase of serum cholesterol than in the controls which received cholesterol-containing food without benzarone. The development of plaques could not be prevented by benzarone, however, the growth of the atheromatous plaque was inhibited and the incorporation of lipids into the plaques was less pronounced than in those animals which received a diet with cholesterol but without benzarone. In those animals which received benzarone more lipid-laden foam cells were seen moving through the endothelium out of the plaque into the lumen of the stimulated artery. These foam cells were of mononuclear origin.

Topics: Animals; Anticholesteremic Agents; Arteriosclerosis; Benzbromarone; Benzofurans; Cholesterol; Electrodes, Implanted; In Vitro Techniques; Rabbits

Topics: Benzbromarone; Benzofurans; Chromatography, High Pressure Liquid; Half-Life; Humans; Kinetics