Disease relevance of Benzbromaron

• Mechanisms of benzarone and benzbromarone-induced hepatic toxicity [1].
• 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) [2].
• Fatal fulminant hepatic failure associated with benzbromarone [3].
• The uricosuric benzbromarone is more effective than allopurinol (ES = 1.50 (0.76 to 2.24)) and can be used in patients with mild to moderate renal insufficiency but may be hepatotoxic [4].
• Renal function improved and no case of renal lithiasis was observed among benzbromarone treated patients, whose mean final dose was 76 mg/day [5].

High impact information on Benzbromaron

• 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 [1].
• The findings indicate that SLC22A12 was responsible for most renal hypouricemia and that URAT1 is the primary reabsorptive urate transporter, targeted by pyrazinamide, benzbromarone, and probenecid in vivo [6].
• CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variant [7].
• 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 [7].
• In addition, the R108F mutation abrogated the Type I difference spectra induced by flurbiprofen and benzbromarone, obligate anions at physiological pH [8].

Chemical compound and disease context of Benzbromaron

• Biotransformation and uric acid lowering effect of benzbromarone in patients with liver cirrhosis - evidence for active benzbromarone metabolites [9]?

Biological context of Benzbromaron

• The order of the IC50 of urate transport via hOAT1 was benzbromarone < probenecid < salicylate or pyrazine carboxylic acid [10].
• The maximum uricosuric response to benzbromarone, equated with the minimum secretory rate, amounted to 50% of the filtered load in normal persons and was lower in gouty normoproducers [11].
• Benzbromarone altered naproxen demethylation kinetics from a biphasic profile to that of a hyperbolic form in CYP2C9.1 and CYP2C9.3, resulting in inhibition and activation, respectively [12].
• Thus, benzbromarone derivatives represent a class of molecules with the potential to reveal more structural details of the 2C9 active site [13].
• The data are compatible with a bimodal or trimodal distribution of different benzbromarone elimination phenotypes [14].

Anatomical context of Benzbromaron

• In vitro inhibition constants (K(i)) of benzbromarone for (S)-warfarin 7-hydroxylation were determined with use of human CYP2C9 and liver microsomes [2].
• The uricosuric drug benzbromarone (3,5-dibromo-4-hydroxyphenyl)-1-(2-ethyl-3-benzofuranyl)methanone, a benzofurane derivative, was studied for its effects on parameters related to hepatic peroxisome proliferation [15].
• By contrast, using the same range of concentrations, human hepatocytes in primary culture treated with benzbromarone revealed no enhancement of enzymatic activity and no concomitant statistically significant increase in the number of peroxisomes; the same observations were reported with clofibric acid and MEHP [16].

Associations of Benzbromaron with other chemical compounds

• A simple MEKC method is described for the separation and quantification of seven widely used uricosuric and antigout drugs, including allopurinol (AP), benzbromarone (BZB), colchicine (COL), orotic acid (OA), oxypurinol (OP), probenecid (PB), and sulfinpyrazone (SPZ) [17].
• Probenecid (PRO), N-ethylmaleimide (NEM) and benzbromarone (BB) moderately (< or = 1.43-fold) but significantly enhanced intracellular accumulation of MRP substrate probes corresponding to MRP expression [18].
• Plasma urate levels and total peroxyl radical-trapping antioxidant parameter (TRAP) for deproteinized plasma in the resting period significantly decreased depending on the treatment, in the order of IMP> control > benzbromarone [19].
• These results indicate that URAT1 is involved in renal reabsorption of oxypurinol, and the increment of renal clearance of oxypurinol upon concomitant administration of benzbromarone could be due to drug interaction at URAT1 [20].
• Excellent uricosuric efficacy of benzbromarone in cyclosporin-A-treated renal transplant patients: a prospective study [21].

Gene context of Benzbromaron

• Benzbromarone, a specific MRP1 inhibitor, decreased the initial efflux rate in 2008/MRP1 cells (4-fold) and in 2008wt cells (2-fold) [22].
• In our efforts to identify agents that would specifically inhibit the two enzymes, benzbromarone and 3',3",5',5"-tetrabromophenolphthalein were found to be relatively selective and potent inhibitors of AKR1C1 [23].
• Charge and substituent effects on affinity and metabolism of benzbromarone-based CYP2C19 inhibitors [24].
• A new class of CYP2C9 inhibitors: probing 2C9 specificity with high-affinity benzbromarone derivatives [13].
• The polarization of fluorescein transport was almost completely abolished by MRP inhibitor, benzbromarone (50 or 100 microM, applied apically), and by MRP/P-glycoprotein inhibitor, verapamil (200 microM, applied apically) [25].

Analytical, diagnostic and therapeutic context of Benzbromaron

• Analysis of benzbromarone in human plasma and urine by high-performance liquid chromatography and gas chromatography-mass spectrometry [26].
• Due to its excellent efficacy and lack of significant side-effects, benzbromarone appears to be preferable to allopurinol in CsA-treated renal transplant recipients with a creatinine clearance over 25 ml/min [21].
• Following oral administration of the uricosuric drug benzbromarone two major metabolites appear in the circulation [27].
• This study was a crossover design consisting of two four-week treatments of allopurinol and benzbromarone separated by a four-week washout period [28].
• Effects of benziodarone and benzbromarone on renal tubular permeability to urate-14C were investigated in anesthetized rats by microinjection and clearance experiments [29].

References