Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan.
J Pharm Biomed Anal. 2023 Aug 5;232:115423. doi: 10.1016/j.jpba.2023.115423. Epub 2023 Apr 26.
Tivozanib is a recently approved tyrosine kinase inhibitor for the treatment of renal cell carcinoma. In this work, two new HPLC methods coupled with fluorescence (FLD), or photodiode array detectors (PDA) were developed and used for the first time for tivozanib quantification in rat plasma and liver microsomes. The described methods were efficient with a 4-min runtime employing a Gemini-NX C column (50 × 2.1 mm, 3 µm) and a mobile phase of acetonitrile and ammonium acetate buffer (pH 4.7, 10 mM) (40:60, v/v) delivered at a flow rate of 0.4 mL/min. The use of HPLC-FLD allowed the quantification of 50 ng/ mL tivozanib using only 100 µL rat plasma. The HPLC-FLD method was validated according to the US food and drug administration (FDA) bioanalytical guidelines and was applied successfully in a rat pharmacokinetic study (n = 7) following oral administration of 1 mg/ kg tivozanib. Furthermore, HPLC-PDA was used for monitoring the depletion of 1 μM (454.9 ng/mL) tivozanib in rat liver microsomes and was applied to study the effect of dexamethasone induction on tivozanib metabolism in vitro. Results showed that dexamethasone enhanced the intrinsic clearance of tivozanib by 60 % suggesting a potential drug-drug interaction at the metabolism level. Dexamethasone is commonly used in the management of cancer disease and thus coadministration with tivozanib therapy may cause treatment failure in patients. The simplicity, speed and cost-effectiveness of the reported methods are ideal for supporting in vivo and in vitro tivozanib studies, including drug-drug interaction studies, particularly in bioanalytical labs lacking LC-MS/MS capabilities.
替沃扎尼布是一种最近批准用于治疗肾细胞癌的酪氨酸激酶抑制剂。在这项工作中，我们首次开发并使用了两种新的 HPLC 方法，分别结合荧光（FLD）或光电二极管阵列检测器（PDA），用于替沃扎尼布在大鼠血浆和肝微粒体中的定量分析。所描述的方法非常有效，运行时间为 4 分钟，使用 Gemini-NX C 柱（50×2.1mm，3µm）和乙腈和乙酸铵缓冲液（pH4.7，10mM）（40:60，v/v）作为流动相，流速为 0.4mL/min。使用 HPLC-FLD 可以仅使用 100µL 大鼠血浆定量 50ng/mL 的替沃扎尼布。HPLC-FLD 方法按照美国食品和药物管理局（FDA）生物分析指南进行了验证，并成功应用于大鼠口服 1mg/kg 替沃扎尼布后的药代动力学研究（n=7）。此外，HPLC-PDA 用于监测大鼠肝微粒体中 1µM（454.9ng/mL）替沃扎尼布的消耗情况，并应用于研究地塞米松诱导对替沃扎尼布体外代谢的影响。结果表明，地塞米松使替沃扎尼布的内在清除率增加了 60%，表明在代谢水平上存在潜在的药物相互作用。地塞米松常用于癌症疾病的治疗，因此与替沃扎尼布联合治疗可能导致患者治疗失败。所报道方法的简单性、速度和成本效益非常适合支持体内和体外替沃扎尼布研究，包括药物相互作用研究，特别是在缺乏 LC-MS/MS 能力的生物分析实验室中。
