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Benzbromarone Pharmacokinetics and Pharmacodynamics in Different Cytochrome P450 2C9 Genotypes

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Benzbromarone Pharmacokinetics and Pharmacodynamics in Different Cytochrome P450 2C9 Genotypes Drug Metab. Pharmacokinet. 25 (6): 605–610 (2010). Note Benzbromarone Pharmacokinetics and Pharmacodynamics in Different Cytochrome P450 2C9 Genotypes Shinya UCHIDA1,*,KayokoSHIMADA2,ShingenMISAKA2, Hiromitsu IMAI3, Yasuhiro KATOH1,NaokiINUI4,KazuhikoTAKEUCHI4,TakashiISHIZAKI4, Shizuo YAMADA2,KyoichiOHASHI3,NoriyukiNAMIKI1 and Hiroshi WATANABE4 1Departments of Pharmacy Practice & Science, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan 2Departments of Pharmacokinetics & Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan 3Department of Clinical Pharmacology & Therapeutics, School of Medicine, Oita University, Oita, Japan 4Department of Clinical Pharmacology & Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: 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 ef- fects. A single oral dose pharmacokinetic and pharmacodynamic trial of benzbromarone (100 mg) was per- formed in 20 healthy volunteers, which included 15 with CYP2C9*1/*1,4withCYP2C9*1/*3,and1with 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 differ- ent CYP2C9 genotypes. These results suggest a critical role for CYP2C9 in the metabolism of benzbroma- rone 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 benzbroma- rone. Keywords: benzbromarone; cytochrome P450 2C9; polymorphism; Pharmacokinetics; uricosuric ef- fect potent uricosuric agent, and has been used for the treat- Introduction ment of hyperuricemia and gout for approximately 30 Hyperuricemia is been associated with cardiovascular years in many countries, particularly those in Europe and diseases in a variety of studies,1–5) andreportedtobe Japan.8–10) However, hepatic dysfunction related to the present in 25% to 50% of individuals with untreated pri- use of benzbromarone has warned,11) to contribute to its mary hypertension, about five times the frequency found withdrawal from the markets of many European coun- in normotensive persons.4) However, whether the level of tries in 2003. Currently, the drug remains available in uric acid in serum is an independent cardiovascular risk some countries in Europe, as well as Brazil, Japan, and factor remains an item of debate.6,7) Benzbromarone is a several other Asian countries.10) Received; April 29, 2010, Accepted; August 5, 2010, J-STAGE Advance Published Date; October 15, 2010 *To whom correspondence should be addressed: Shinya UCHIDA,PhD,Department of Pharmacy Practice & Science, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, 422-8526, Shizuoka, Japan. E-mail: uchidas＠u-shizuoka-ken.ac.jp This work was partially supported by the Japanese Ministry of Health, Labor and Welfare (H16-tyoju–001; Quality use of drugs for elderly based on pharmacogenetic information in Japan). 605 606 Shinya UCHIDA, et al. It is known that the uricosuric effect of benzbroma- Study design: A standardized meal was served from rone and a major metabolite, 6-hydroxybenzbromarone two days before the administration of benzbromarone is based on its inhibition of renal reabsorption of uric until the final day of the study. Using an open-label study acid by proximal tubular cells by inhibiting a urate trans- protocol, a single oral dose (100 mg) of benzbromarone porter (URAT1, encoded by SLC22A12).10,12,13) It was ini- (Urinorm; Torii Pharmaceutical Co. Ltd, Tokyo, Japan) tially thought that debrominate compounds, such as was administered to the 20 subjects after overnight fast- bromobenzarone and benzarone, are the predominant ing. Blood samples were taken just before and at 1, 2, 4, metabolites of benzbromarone. However, two main hy- 6, 8, 11, and 24 hr after administration, and the plasma droxylated metabolites, 1?-hydroxybenzbromarone and levels of uric acid were analyzed before and 24 hr after 6-hydroxybenzbromarone, and not bromobenzarone and benzbromarone administration. In addition, uric acid lev- benzarone, have been detected in plasma and urine sam- els in 24-hr urine samples were determined before and ples of volunteers after a single oral administration.14–16) after benzbromarone administration. It has been reported that the half-life of benzbromarone Genotyping: Deoxyribonucleic acid (DNA) was ex- is short, while 6-hydroxybenzbromarone has a much lon- tracted from peripheral whole blood samples and ger half life.17) Recently, in vitro results from a study using CYP2C9 alleles were detected using a polymerase chain human cytochrome P450 (CYP)-expressing microsome reaction (PCR)-restriction fragment length polymor- samples revealed that benzbromarone is metabolized by phism, as previously described.24,25) CYP2C9 and the main metabolite formed was 6-hydrox- Determination of concentrations in plasma and ybenzbromarone.18) However, it has not been shown that urine: The concentrations of benzbromarone, 6- CYP2C9 is involved in the metabolic pathway of ben- hydroxybenzbromarone, benzarone, and bromobenza- zbromarone in humans in vivo. The existence of genetic rone were analyzed by high-performance liquid chro- polymorphisms of CYP2C9 has been recognized to in- matography-tandem mass spectrometry. Briefly, urine fluence the activity of the enzyme and clinical conse- was pretreated with b-glucuronidase. As an internal stan- quence,19) and human studies have demonstrated that the dard, indomethacin (20 ng) was added to plasma and u- CYP2C9*3 (1075AÀC, Ile359Leu) variant is associated rine samples, then extracted using diethyl with poor metabolism related to classic CYP2C9 sub- ether/dichloromethane (7:3, v/v). High-performance liq- strates, such as tolbutamide,20) glibenclamide,21) and uid chromatography was performed using an analytical 22) warfarin. The elimination of benzbromarone has been column (Symmetry C18,2.1×150 mm, 5.0 mm, Waters, shown to have large inter-individual differences.14,23) Milford, Mass), with the mobile phase (acetonitril/0.1% However, the clinical impact of different CYP2C9 geno- formic acid, 60/40, v/v) delivered at a flow rate of 0.2 types on the pharmacokinetics and uricosuric effect of ml/min. Mass spectrometry was performed with at- thedrug(i.e., pharmacodynamics) has not been clarified. mospheric pressure chemical ionization in negative ion Thus, the aims of the present study were to assess the detection mode. The ion transition monitored was mass- clinical impact of CYP2C9 genotypes on the pharmacoki- to-charge ratio, which was from 422.9 to 250.8 m/z for netics and pharmacodynamics of benzbromarone, and to benzbromarone, 438.9 to 250.7 m/z for 6-hydroxyben- evaluate whether CYP2C9 plays a critical role in its zbromarone, 464.9 to 93.0 m/z for benzarone, 244.9 to metabolism. 81.0 m/z for bromobenzarone, and 356.0 to 312.0 m/z for indomethacin. The limits of detection were 10 ng/ml Materials and Methods for benzbromarone and 6-hydroxybenzbromarone, and Subjects: CYP2C9 genotype status was screened in 1.0 ng/ml for benzarone and bromobenzarone. The in- 144 healthy Japanese volunteers. After the screening, 20 ter-assay coefficients of variation were º15.6% for all healthy volunteers (age range, 20–30 years old; body compounds. weight range, 49.3–71.2 kg), which included 15 with Data analysis: The pharmacokinetic parameters of CYP2C9*1/*1,4withCYP2C9*1/*3,and1with benzbromarone were calculated by non-compartmental CYP2C9*3/*3, were enrolled in this study as subjects. The analysis using WinNonlin (version 4.1, Pharsight, Moun- CYP2C9*2 allele was not detected in any of the geno- tain View, Calf). The metabolic ratio (ratio of amount for typed volunteers. All subjects were in good health, as in- 6-hydroxybenzbromarone to that for benzbromarone) dicated by medical history, and routine physical examina- was calculated using the post-administration 24-hr urine tion and clinical laboratory test results. No medications samples. Changes in the urinary excretion and plasma including herbal drugs and beverages containing concentration of uric acid were used to determine the grapefruit products were permitted throughout the study pharmacodynamic effect of benzbromarone. period. The study protocol was approved by the Ethics Statistical analysis: All data are presented as means Committee of Hamamatsu University School of Medicine and SD. GraphPad Prism (version 3.03, GraphPad and that of University of Shizuoka. All subjects gave writ- Software, San Diego, Calf) was used for all statistical ana- ten informed consent before enrollment. lyses. A Mann-Whitney test and paired t-test were used to Benzbromarone and CYP2C9 Genotype 607 assess differences
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