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At least 19 recordsLinked to original sources
PubMed1995

Biotransformation and uric acid lowering effect of benzbromarone in patients with liver cirrhosis - evidence for active benzbromarone metabolites?

The disposition of benzbromarone and its uric acid lowering effect were investigated in 8 patients with compensated liver cirrhosis in order to obtain evidence whether dose requirements differ from subjects with normal liver function. Following a single oral dose of 100 mg benzbromarone, the plasma concentrations of the parent drug and the two hydroxylated main metabolites M1 and M2 as well as uric acid were determined up to at least 72 h. All patients were found to be rapid benzbromarone eliminators. In patients 2-8 the extent of systemic availability of benzbromarone, as estimated by the average AUC(0-infinite), was similar to previous observations in healthy individuals, whereas the values of both metabolites M1 and M2 tended to be lower in patients with liver cirrhosis. Cmax of benzbromarone and M1 also were lower in patients, M2 was equivalent to the data in subjects with normal liver function. tmax and the plasma elimination half-life t(1/2) varied within the same range as previously observed in healthy individuals. One patient exhibited much higher values in AUC(0-infinite); and Cmax of benzbromarone and both metabolites, and in addition of the elimination half-life of M1 and M2, whereas the plasma elimination of benzbromarone itself was not delayed. An effect of altered liver function cannot be excluded in this patient. Ten hours after benzbromarone administration the mean plasma uric acid in patients 2-8 was reduced by 31.5% and in patient 1 by 44.2% as compared to pretreatment values. Baseline levels were not regained until 72 h. These data are compatible with a prolonged uric acid lowering effect of an active benzbromarone metabolite. Altogether, the present observations do not suggest dose adjustment to be necessary in patients with compensated liver cirrhosis Child A and B.

Adult↗
PubMed1990

Rapid and slow benzbromarone elimination phenotypes in man: benzbromarone and metabolite profiles.

Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation. 1'-hydroxy-benzbromarone (M1), and a second product (M2) of unknown structure. The plasma concentrations of the parent drug and of M1 and M2 have now been compared in two different elimination phenotypes. 10 subjects who eliminated the drug rapidly (S1-10) and one individual (S11) whose elimination capacity was impaired, presumably due to genetic variation (S11). The AUC (0-96) of the parent drug in S11 was 145 micrograms.ml-1 h. and in the other individuals it averaged 18.3 (11.4-24.5) micrograms.ml-1 h. The plasma elimination half life of benzbromarone was 3.34 (1.77-5.24) h in the rapid eliminators, and 13.08 h in the subject with the elimination defect. The mean plasma elimination half life of the metabolites in S1-10 amounted to 20.1 (11.9-41.2) h for M1, and 17.2 (12.9-30.7) h for M2. In S11 the plasma elimination half life of M1 was prolonged to 76.6 h, and of M2 to 75.4 h. Thus, the elimination defect in S11 was not restricted to the parent drug, but it also involved the two major metabolites M1 and M2. This might be a consequence of a hepatic enzyme deficiency, or be due to impairment of drug excretion.

Adult↗
PubMed1993

Metabolism of benzbromarone in man: structures of new oxidative metabolites, 6-hydroxy- and 1'-oxo-benzbromarone, and the enantioselective formation and elimination of 1'-hydroxybenzbromarone.

1. The uricosuric drug benzbromarone is extensively metabolized in man and two main metabolites are formed: the previously characterized 1'-hydroxybenzbromarone (metabolite M1) and an arylhydroxybenzbromarone (metabolite M2) of unknown structure. A dimethyl derivative was isolated from urine after methylation and was characterized by gas chromatography-mass spectrometry (g.l.c.-m.s.) and high resolution nuclear magnetic resonance spectroscopy as 4''-O-methyl-6-methoxybenzbromarone; the structure of M2 therefore is 6-hydroxybenzbromarone. 2. A minor metabolite was similarly characterized as 1'-oxobenzbromarone by comparison with authentic synthetic samples and is a product of biodegradation and not an artifact derived from the in vitro oxidation of 1'-hydroxybenzbromarone. Further minor metabolites were detected and were provisionally characterized by g.l.c.-m.s. after derivatization and include: 2'-hydroxybenzbromarone (an isomer of 1'-hydroxybenzbromarone); 1',6-dihydroxybenzbromarone; dihydroxy-aryl-benzbromarone; and two structure isomers of 6-hydroxybenzbromarone. Debrominated metabolites were not detectable. 3. Benzbromarone is hydroxylated in vivo at the prochiral centre C1' to 1'-hydroxybenzbromarone; analysis of 1'-hydroxybenzbromarone from plasma and urine extracts by h.p.l.c. using a chiral column revealed that two peaks were eluted which showed a mean enantiomeric ratio of 2.1 for plasma and 7.3 for urine; these data demonstrate that the formation and elimination of this metabolite is enantioselective; the absolute configuration of the 1'-chiral centre is presently unknown.

Adult↗
PubMed1981

[Determination of benzbromarone in serum following combined therapy with allopurinol and benzbromarone (author's transl)].

A rapid method is described for benzbromarone assay in human serum. Protein precipitation is followed by extraction of the active substance. After centrifugation the clear organic layer is evaporated to dryness, redissolved in methanol and injected on a HPLC-column. Detection limits for this method of assay are 0.1 microgram benzbromarone/ml serum. The blood level for therapeutic concentrations lies between 1 and 2.5 microgram/ml. Some pharmacokinetic data were presented. The half-life of benzbromarone is 2.6 h.

Adult↗
PubMed2005

Mechanisms of benzarone and benzbromarone-induced hepatic toxicity.

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.

Amiodarone↗
PubMed1999

Potentiation of anticoagulant effect of warfarin caused by enantioselective metabolic inhibition by the uricosuric agent benzbromarone.

OBJECTIVE: To clarify the mechanism(s) for the interaction between warfarin and benzbromarone, a uricosuric agent, and to predict changes in the in vivo pharmacokinetics of (S)-warfarin from in vitro data. METHODS: Warfarin enantiomers and benzbromarone in serum, 7-hydroxywarfarin in urine, and serum unbound fractions of warfarin enantiomers were measured in patients with heart disease given warfarin with (n = 13) or without (n = 18) oral benzbromarone (50 mg/d). In vitro inhibition constants (K(i)) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes. The magnitude of changes in the formation clearance for 7-hydroxylation (CLf), the unbound oral clearance (CL(oral,u)), and the oral clearance (CL(oral)) for (S)-warfarin were predicted by equations incorporating the in vitro Ki, the theoretical maximum unbound hepatic benzbromarone concentration, and the fractions of warfarin eliminated through metabolism and of CYP2C9-mediated metabolic reaction susceptible to inhibition by benzbromarone. RESULTS: The patients given warfarin with benzbromarone required a 36% less (P < .01) warfarin dose than those given warfarin alone (2.5 versus 3.9 mg/d) to attain similar international normalized ratios (2.1 and 2.2, respectively), and the former had 65%, 53%, and 54% lower (P < .05 or P < .01) CLf, CL(oral),u, and CL(oral) for (S)-warfarin than the latter, respectively. In contrast, no significant differences were observed for (R)-warfarin kinetics between the groups. Benzbromarone was found to be a potent competitive inhibitor (Ki < 0.01 micromol/L) for (S)-warfarin 7-hydroxylation mediated by CYP2C9. The average changes in the in vivo CLf, CL(oral),u, and CL(oral)values for (S)-warfarin induced by benzbromarone were largely predictable by the proposed equations. CONCLUSION: Benzbromarone would intensify anticoagulant response of warfarin through an enantioselective inhibition of CYP2C9-mediated metabolism of pharmacologically more potent (S)-warfarin. The magnitude of changes in the in vivo warfarin kinetics may be predicted by in vitro data.

Aged↗
PubMed1988

Benzbromarone disposition and uricosuric action; evidence for hydroxilation instead of debromination to 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.

Adult↗
PubMed2005

CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variant.

The CYP2C9.3 variant exhibits marked decreases in substrate turnover compared with the wild-type enzyme, but little is known regarding the effect this variant form may have on the occurrence of drug-drug interactions. To examine this possibility, the effect of the potent CYP2C9 inhibitor, benzbromarone, was studied with regard to CYP2C9.1- and CYP2C9.3-mediated flurbiprofen metabolism to evaluate whether the variant enzyme exhibits differential inhibition kinetics. Although benzbromarone inhibited CYP2C9.1 activity as expected, CYP2C9.3-mediated flurbiprofen 4'-hydroxylation was activated in the presence of benzbromarone. T1 relaxation studies revealed little change in distances of flurbiprofen protons from the heme iron of either CYP2C9.1 or CYP2C9.3 in the presence of benzbromarone compared with flurbiprofen alone. Spectral binding studies were also performed to investigate whether benzbromarone affected substrate binding, with the addition of benzbromarone having little effect on flurbiprofen-binding affinity in both CYP2C9.1 and CYP2C9.3. Docking studies with the 2C9.1 structure crystallized with a closed active site identified multiple but overlapping subsites with sufficient space for benzbromarone binding in the enzyme when flurbiprofen was positioned closest to the heme. If the closed conformation of 2C9.3 is structurally similar to 2C9.1, as expected for the conservative I359L mutation, then the dynamics of benzbromarone binding may account for the switching of drug interaction effects. In conclusion, the I359L amino acid substitution found in CYP2C9.3 not only reduces metabolism compared with CYP2C9.1 but can also dramatically alter inhibitor effects, suggesting that differential degrees of drug inhibition interactions may occur in individuals with this variant form of CYP2C9.

Aryl Hydrocarbon Hydroxylases↗
PubMed1996

Enhancement of anticoagulant action by warfarin-benzbromarone interaction.

To investigate the interaction between warfarin potassium and benzbromarone, administration of benzbromarone to patients receiving long-term treatment with both drugs was discontinued for 1 week and then resumed, and the resulting changes in the coagulation system were examined. Thrombotest value, activity of coagulation factors II and VIII, concentration of protein induced by vitamin K absence or antagonist-II (PIVKA-II), total plasma concentration of warfarin, and free warfarin concentration were measured during the period of concurrent administration of the two drugs, 1 week after discontinuation of benzbromarone, and after resumption of benzbromarone administration. After administration of benzbromarone had been discontinued for 1 week, the thrombotest value and factor II activity rose significantly whereas PIVKA-II activity dropped significantly compared with corresponding levels before discontinuation, but these parameters tended to revert to the previously maintained levels after resumption of benzbromarone treatment. Activity of the vitamin K-independent factor VIII displayed almost no changes, however. Total plasma warfarin concentration also decreased significantly, and free warfarin concentration was nearly unchanged. These results verified that the anticoagulant action of warfarin is enhanced by concurrent administration of benzbromarone. Accordingly, adequate consideration must be devoted to the prevention of grave hemorrhagic tendencies when these two drugs are administered concurrently.

Aged↗
PubMed1993

Benzbromarone hydroxylation in man: defective formation of the 6-hydroxybenzbromarone metabolite.

To determine the elimination phenotype of the uricosuric agent benzbromarone 100 mg of the drug was administered as a single oral dose to 11 volunteers on a formula diet; plasma concentration-time profiles of the parent drug and the main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxy-benzbromarone) were measured by high-performance liquid chromatography for 168 h. Of the 11 subjects 2 showed higher plasma concentrations and delayed elimination of benzbromarone and metabolite M1 but reduced formation of metabolite M2 compared to the other 9 subjects. However, the plasma concentration-time profiles of the metabolites in these two slow eliminators, termed type 2, differed from those of a poor eliminator characterized during a previous study; the latter, termed type 1, eliminated benzbromarone as well as both metabolites M1 and M2 slowly. The differences in the elimination of benzbromarone and its metabolites are probably caused by differences in the activities of the cytochrome P450 mono-oxygenase isozymes. The results show that determination of the phenotype solely by measurement of the 24-h benzbromarone plasma concentration does not unequivocally characterize slow benzbromarone eliminators; additional plasma concentration-time profiles of the parent drug and metabolites are necessary. Metabolite M2 is characterized as 6-hydroxybenzbromarone; the formation and elimination of the chiral metabolite M1 is enantioselective.

Administration, Oral↗
PubMed1990

Analysis of uric acid transport in renal tubules using benzbromarone and pyrazinamide.

Both the benzbromarone loading test alone and the pyrazinamide suppression test combined with the benzbromarone loading test were performed in four healthy male volunteers to examine the renal handling of uric acid and to demonstrate whether benzbromarone selectively blocks postsecretory reabsorption. On the basis of the four-component theory, equations of four states of fractional uric acid clearance were constructed: 1) the control state, the states of 2) benzbromarone loading, 3) pyrazinamide suppression and 4) both pyrazinamide suppression and benzbromarone loading. As a result, presecretory reabsorption, tubular secretion and postsecretory reabsorption of uric acid were calculated to be about 93-98%, 30-44% and 79-92%, respectively. In addition, it was calculated that benzbromarone inhibited postsecretory reabsorption selectively. Because of the selectivity of the action site of benzbromarone in renal tubules, this loading test is considered to reflect uric acid transport more precisely than tests using probenecid.

Benzbromarone↗
PubMedDate not supplied

Clinical evaluation of benzbromarone: a new uricosuric drug.

The long-term efficacy and safety of benzbromarone were studied in 21 nontophaceous hyperuricemic men. Daily doses of 40 or 80 mg of micronized benzbromarone caused a rapid fall in plasma urate which was maintained throughout a study period that lasted up to 1 year. A concomitant marked increase in the clearance of urate indicated that benzbromarone is a potent uricosuric drug. Initial treatment was accompanied by transient hyperuricosuria, following which urinary uric acid reverted toward, but failed to reach completely, pretreatment values. Benzbromarone did not inhibit xanthine oxidase nor did it influence the activity of purine phosphoribosyl transferases. These observations suggest that benzbromarone has no direct effect upon purine metabolic pathways, but exerts its hypouricemic action solely by blocking tubular reabsorption of uric acid. Concomitant administration of aspirin interfered only slightly with the uricosuric properties of benzbromarone. No side effects directly attributable to the drug were observed.

Adult↗
PubMed1998

Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout.

OBJECTIVES: To study the efficacy of allopurinol and benzbromarone to reduce serum urate concentrations in patients with primary chronic gout. METHODS: Prospective, parallel, open study of 86 consecutive male patients with primary chronic gout. Forty nine patients (26 normal excretors and 23 under excretors) were given allopurinol 300 mg/day and 37 under excretors benzbromarone 100 mg/day. After achieving steady plasma urate concentrations with such doses, treatment was then adjusted to obtain optimal plasmatic urate concentrations (under 6 mg/dl). RESULTS: Patients receiving allopurinol 300 mg/day showed a mean reduction of plasmatic urate of 2.75 mg/dl (from 8.60 to 5.85 mg/dl) and 3.34 mg/dl (from 9.10 to 5.76 mg/dl) in normal excretors and under excretors respectively. Patients receiving benzbromarone 100 mg/day achieved a reduction of plasmatic urate of 5.04 mg/dl (from 8.58 to 3.54 mg/dl). Fifty three per cent of patients receiving allopurinol and 100% receiving benzbromarone achieved optimal plasma urate concentrations at such doses. The patients with poor results with allopurinol 300 mg/day achieved a proper plasma urate concentration with allopurinol 450 to 600 mg/day, the mean final dose being 372 mg/day. Renal function improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day. CONCLUSION: Benzbromarone is very effective to control plasma urate concentrations at doses ranging from 50 to 100 mg/day. Uricosuric treatment is a suitable approach to the treatment of patients with gout who show underexcretion of urate.

Adult↗
PubMed2002

Efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients.

This study was aimed to evaluate the efficacy of benzbromarone compared to allopurinol in lowering serum uric acid level in hyperuricemic patients with normal renal function (serum creatinine < or = 1.5). The authors conducted a crossover study consisting of two four-week treatment periods of allopurinol 300 mg/day and benzbromarone 100 mg/day separated by a four-week washout period. Fourteen patients with mean age and duration of hyperuricemia of 60.78 +/- 8.62 and 6.93 +/- 3.69 years, respectively, were recruited and all completed our study protocol. This study was a crossover design consisting of two four-week treatments of allopurinol and benzbromarone separated by a four-week washout period. The serum uric acid level was reduced from 9.89 +/- 1.43 mg/dl to 5.52 +/- 0.83 mg/dl and from 9.53 +/- 1.48 to 4.05 +/- 0.87 mg/dl by allopurinol and benzbromarone, respectively. The efficacy of benzbromarone in lowering serum uric acid level was significantly superior to allopurinol (p=0.005). No patient reported clinical side effects during treatment with either drug. In conclusion, the authors have shown that benzbromarone is more effective than allopurinol in the reduction of serum uric acid levels in hyperuricemic patients with normal renal function.

Adult↗
PubMed1990

Urinary metabolites of benzbromarone in man.

Benzbromarone [3,5-dibromo-4-hydroxyphenyl)-(2-ethyl-3-benzofuranyl)-ketone) is a widely used uricosuric drug which was reported to be metabolized by successive debromination. Recently, however, it was reported that benzbromarone is not debrominated but hydroxylated at the ethyl side chain. The presented paper describes further studies on the metabolism of the drug in man. The metabolites were identified in urine samples from two different patients intoxicated suicidally with high doses of benzbromarone after cleavage of conjugates, extraction and derivatization by acetylation using gas chromatography-mass spectrometry. The following five metabolites could be identified besides the unchanged benzbromarone (BB): hydroxy-alkyl-BB, oxo-BB, two isomers of hydroxyaryl-BB and hydroxy-methoxy-aryl-BB. Therefore, the following two phase I metabolic pathways can be postulated: successive oxidation of the ethyl side chain and one- and twofold hydroxylation of the benzofuran ring followed by methylation of one of the hydroxy groups. Benzbromarone and its metabolites are excreted in urine partly in a conjugated form. Debrominated metabolites could not be detected, although the concentrations of benzbromarone and its metabolites were very high in the urine samples studied.

Acetylation↗
PubMed1990

Variation of benzbromarone elimination in man--a population study.

The plasma benzbromarone concentration-time profile in a healthy subject who retained the compound much longer than other individuals is described. The data suggested that determination of the 24 h plasma concentration of the parent drug after a single oral dose of 100 mg benzbromarone would be an appropriate procedure to determine the elimination phenotype. Based on this procedure, 148 of 153 healthy individuals (97%) in a population study were found to eliminate benzbromarone rapidly. In one subject the 24 h benzbromarone plasma concentration was very similar to that observed in the individual who had been more fully characterized. Four participants gave intermediate results. The data are compatible with a bimodal or trimodal distribution of different benzbromarone elimination phenotypes.

Adult↗
PubMed1993

The effect of benzbromarone on allopurinol/oxypurinol kinetics in patients with gout.

The objectives of this study were to establish if, and to what extent, benzbromarone affects allopurinol/oxypurinol kinetics, and to compare the uric acid lowering capabilities of Allomaron (allopurinol 100 mg plus benzbromarone 20 mg) with the effects of allopurinol alone in patients with confirmed gout. We studied 14 adult men in an open randomized cross-over study. After a 14 day run-in period with Zyloprim (2 x 100 mg allopurinol tablets in the morning), the patients were randomly allocated to morning doses of either Allomaron (2 tablets) or Zyloprim (2 tablets). Seven days later cross-over was effected and the alternative treatment was taken for a further 7 days. On days 7 and 14 the patients came into hospital and venous blood samples were taken over 24 h for allopurinol and oxypurinol assays by HPLC. Serum uric acid was determined on days -14, 1, 7, and 14. Benzbromarone lowered plasma oxypurinol concentrations (Allomaron/Zyloprim mean ratio of AUC0-->24 was 59%; 95% confidence interval 54-64%), but did not affect plasma allopurinol concentrations. Despite this pharmacokinetic interaction of benzbromarone with allopurinol, resulting in lower plasma concentrations of oxypurinol, Allomaron was superior to allopurinol alone in lowering serum uric acid, probably because of the added uricosuric effect of benzbromarone.

Adult↗