Benzbromarone Pharmacokinetics and Pharmacodynamics in Différent Cytochrome P450 2C9 Genotypes

Abstract

Benzbromarone is a uricosuric drug and has been shown to be metabolized predominantly by cytochrome P450(CYP)2C9 in vitro findings. This study aims to investigate the influence of the CYP2C9 genotype on plasma levels of benzbromarone and 6-hydroxybenzbromarone, as well as uric acid lowering effects. A single oral dose pharmacokinetic and pharmacodynamic trial of benzbromarone (100 mg) was performed in 20 healthy volunteers, which included 15 with CYP2C9*1/*1, 4 with CYP2C9*1/*3, and 1 with CYP2C9*3/*3. The oral clearance of benzbromarone in the CYP2C9*1/*1 genotype and CYP2C9*1/*3 genotype was 58.8±25.2 L/hr/kg (mean±SD) and 51.3±7.9 L/hr/kg, respectively, whereas 8.58 L/hr/kg in the CYP2C9*3/*3 genotype. The metabolic ratio (6-hydroxybenzbromarone/benzbromarone) in urine was 38.6±10.7 in the CYP2C9*1/*1 genotype, 35.4±12.4 in the CYP2C9*1/*3 genotype and 12.9 in the CYP2C9*3/*3 genotype. Although benzbromarone significantly increased the urinary excretion and reduced the plasma concentration of uric acid, there were no significant differences in its effects for different CYP2C9 genotypes. These results suggest a critical role for CYP2C9 in the metabolism of benzbromarone in humans and a possible risk of toxicity in the CYP2C9*3 homozygote by lowering clearance of the drug. Further studies are required to assess the clinical impact of CYP2C9 on the metabolism of benzbromarone.

The genetics of gout: towards personalised medicine?

“…CYP2C9*3 homozygotes have a markedly longer benzbromarone elimination half-life than other CYP2C9 genotypes, which may increase the risk of benzbromarone-induced hepatotoxicity [66]. The frequency of CYP2C9 poor metaboliser alleles is substantially higher in Europeans compared to Polynesians [67].…”

Structure-Activity Relationships of Benzbromarone Metabolites and Derivatives as EYA Inhibitory Anti-Angiogenic Agents

“…6OH-BBR is a major metabolite of BBR and has a much longer half-life (30 hours relative to 3 hours for BBR as previously reported [24,29]) raising the interesting possibility that, in the context of angiogenesis, BBR may act as a pro-drug with biotransformation into 6OH-BBR yielding a pharmacologically active metabolite. It also suggests that polar substituents at position 6 of the benzofuran would yield more effective anti-angiogenic agents.…”

Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

“…Previously reported C max and unbound fraction values in plasma were obtained for 17 known inhibitors of CYP2C8 (benzbromarone, candesartan, candesartan cilexetil, clotrimazole, 17a-ethynylestradiol, fluconazole, itraconazole, mometasone furoate, montelukast, pioglitazone, quercetin, raloxifene, repaglinide, ritonavir, rosiglitazone, tamoxifen and zafirlukast) at clinically relevant doses [64][65][66][67][68][69][70][71][72][73] . As no reported plasma concentrations of clotrimazole after oral administration were available, skin concentrations following a topical administration were used.…”