A sensitive HPLC-FL method to simultaneously determine febuxostat and diclofenac in rat plasma: assessment of metabolic drug interactions in vitro and in vivo,Analytical Methods

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A sensitive HPLC-FL method to simultaneously determine febuxostat and diclofenac in rat plasma: assessment of metabolic drug interactions in vitro and in vivo
Analytical Methods ( IF 2.7 ) Pub Date : 2020-04-01 , DOI: 10.1039/d0ay00471e
Dong-Gyun Han _{1,

2,

3,

4,

5} , Kyu-Sang Kim _{5,

6,

7,

8} , Seong-Wook Seo _{1,

2,

3,

4,

5} , Young Mee Baek _{3,

4,

5,

9} , Yunjin Jung _{1,

2,

3,

4,

5} , Dae-Duk Kim _{5,

6,

7,

8} , In-Soo Yoon _{1,

2,

3,

4,

5}

Affiliation

Febuxostat (FEB) is a selective xanthine oxidase (XO) inhibitor approved for chronic management of hyperuricemia (HU) in patients with gout. Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac (DIC) are the first choice for the prevention and treatment of gouty inflammation and flare. In this study, a sensitive and simple bioanalytical method using HPLC coupled with a fluorescence detector (HPLC-FL) was developed for the simultaneous determination of FEB and DIC. The linearity (1–1500 ng mL⁻¹ for FEB and 5–1500 ng mL⁻¹ for DIC), precision, accuracy, recovery, matrix effect, and stability of the newly developed method were validated as per the US Food and Drug Administration (FDA) guidelines. Next, the in vivo and in vitro metabolic interactions between FEB and DIC were comprehensively examined. The in vivo pharmacokinetics of FEB were found to be significantly altered by the co-administration of DIC in rats. Further, the in vitro microsomal metabolism study revealed that the altered pharmacokinetics of FEB could be attributed primarily to the competitive inhibition of FEB metabolism by DIC. To our knowledge, this is the first systematic study showing the in vivo pharmacokinetic interaction of FEB with DIC following intravenous and oral administration in rats and the associated metabolic inhibition mechanism together with a new HPLC-FL method to simultaneously determine FEB and DIC in biological matrices.

中文翻译：

同时测定大鼠血浆中非布索坦和双氯芬酸的灵敏HPLC-FL方法：评估体内外代谢药物的相互作用

非布索坦（FEB）是一种选择性的黄嘌呤氧化酶（XO）抑制剂，已批准用于痛风患者的慢性高尿酸血症（HU）的慢性治疗。非甾体类抗炎药（NSAID），例如双氯芬酸（DIC），是预防和治疗痛风性炎症和眩光的首选。在这项研究中，开发了一种灵敏且简单的生物分析方法，该方法使用HPLC结合荧光检测器（HPLC-FL）来同时测定FEB和DIC。线性度（1-1500毫微克毫升^-1为FEB和5-1500毫微克毫升^-1为DIC），精度，准确度，回收率，基体效应，和稳定性的新开发的方法的进行了验证按照美国食品和药品管理局（FDA）准则。接下来，体内和体外全面检查了FEB和DIC之间的代谢相互作用。在体内被发现FEB的药代动力学在大鼠DIC的联合政府将显著改变。此外，体外微粒体代谢研究表明，FEB的药代动力学改变可能主要归因于DIC对FEB代谢的竞争性抑制。据我们所知，这是第一项系统研究，表明大鼠静脉内和口服给药后FEB与DIC的体内药代动力学相互作用以及相关的代谢抑制机制以及新的HPLC-FL方法可同时测定生物基质中的FEB和DIC 。

更新日期：2020-04-01

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