Effects of UDP-glucuronosyltransferase (UGT) polymorphisms on the pharmacokinetics of febuxostat in healthy Chinese volunteers

• Published in: Drug metabolism and pharmacokinetics Vol. 32; no. 1; pp. 77 - 84
• Main Authors: Lin, Meihua, Liu, Jian, Zhou, Huili, Wu, Minglan, Lv, Duo, Huang, Yujie, Zheng, Yunliang, Shentu, Jianzhong, Wu, Lihua
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2017
• Subjects: Administration, Oral; Adult; China; Cross-Over Studies; Febuxostat; Febuxostat - administration & dosage; Febuxostat - chemistry; Febuxostat - pharmacokinetics; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Healthy Volunteers; Humans; Male; Pharmacokinetics; Polymorphism, Genetic - genetics; Polymorphisms; Retrospective Studies; UGT1A1; UGT1A3; Young Adult; UGT1A3; UGT1A1; Pharmacokinetics; Polymorphisms; Febuxostat
• ISSN: 1347-4367; 1880-0920
• DOI: 10.1016/j.dmpk.2016.08.003

The pharmacokinetics (PKs) of febuxostat varies among individuals, while the main causes are still unknown. We investigated whether the polymorphisms of UGT1A1 and UGT1A3 played an important role in the disposition of the drug after oral administration of febuxostat tablet in Chinese subjects. A total of 42 healthy subjects were from two previous independent clinical bioequivalence (BE) trials of febuxostat, in which the same reference formulation (ULORIC® tablet, 80 mg) was taken, and thus the PK data were combined for the evaluation of pharmacogenomic effect on febuxostat PKs. Our study clearly indicated that the area under the plasma concentration-time curve (AUC) in the heterozygote and homozygote of UGT1A1*6 (c.211G > A, rs4148323) was significantly higher than that in the wild-type. Meanwhile, the clearance (CL/F) exhibited a significant reduction by 22.2%. Interestingly, UGT1A1*28, in perfect linkage disequilibrium (LD) with UGT1A3*2a, significantly increased its clearance. These results indicate that UGT1A1*6 was an important factor influencing the drug disposition, thus providing a probable explanation for interindividual variation of febuxostat PKs in Chinese subjects. In addition, by considering of the different allele distribution of UGT1A1*6 and *28 in Eastern and Western populations, these findings might further interpret the ethnic difference of febuxostat PKs.