Benzbromarone pharmacokinetics and pharmacodynamics in different cytochrome P450 2C9 genotypes.
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.
Department of Pharmacy Practice & Science, School of Pharmaceutical Sciences, University of Shizuoka, Suruga-ku, Shizuoka, Japan. uchidas＠u-shizuoka-ken.ac.jp
Shinya
S
Uchida
Kayoko
K
Shimada
Shingen
S
Misaka
Hiromitsu
H
Imai
Yasuhiro
Y
Katoh
Naoki
N
Inui
Kazuhiko
K
Takeuchi
Takashi
T
Ishizaki
Shizuo
S
Yamada
Kyoichi
K
Ohashi
Noriyuki
N
Namiki
Hiroshi
H
Watanabe
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001553:Benzbromarone / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000652:urine; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D014528:Uricosuric Agents / Q000493:pharmacokinetics
C085923:6-hydroxybenzbromarone; D014528:Uricosuric Agents; D001553:Benzbromarone; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases