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Rapid determination of the pharmacokinetics and metabolic fate of gefitinib in the mouse using a combination of UPLC/MS/MS, UPLC/QToF/MS, and ion mobility (IM)-enabled UPLC/QToF/MS
Xenobiotica ( IF 1.3 ) Pub Date : 2021-02-08 , DOI: 10.1080/00498254.2020.1859643
Billy J Molloy 1 , Adam King 1 , Lauren Mullin 1 , Lee A. Gethings 1 , Robert Riley 2 , Robert S Plumb 3 , Ian D Wilson 4
Affiliation  

Abstract

  1. The metabolism and pharmacokinetics of gefitinib (Iressa®, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholino-propoxy)quinazolin-4-amine), a selective thymidylate kinase inhibitor for the epidermal growth factor receptor (EGFR), was studied after IV and PO administration to male C57BL6 mice at 10 and 50mg/kg respectively.

  2. The pharmacokinetics and metabolism of gefitinib were investigated using a range of rapid UHPLC-MS and UHPLC-IM-HRMS methods, using both reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC), to rapidly determine the drugs pharmacokinetics and metabolic fate.

  3. Rapid oral absorption resulted in peak plasma concentrations at 1h of ca. 7µg/mL, that declined with a half-life of 3.8h (2.6h for the IV route), and providing an estimated oral bioavailability of 53%. Gefitinib itself was the major circulating drug-related compound in plasma extracts, with a total of 11 metabolites identified.

  4. The urinary profiles determined using both HILIC and RP-UPLC-IM-MS detected gefitinib and 10 metabolites or 15 metabolites respectively including the detection of a number of novel glucuronide conjugates.

  5. Despite rapid, sub 5min, LC profiling methods being employed metabolite coverage was shown to be high and compared well with that of previous studies.



中文翻译:

使用UPLC / MS / MS,UPLC / QToF / MS和启用离子迁移(IM)的UPLC / QToF / MS的组合快速测定吉非替尼在小鼠中的药代动力学和代谢命运

抽象的

  1. 代谢和吉非替尼的药物动力学(易瑞沙®为表皮,N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-吗啉代丙氧基)喹唑啉-4-胺),选择性胸苷酸激酶抑制剂在分别以10和50 mg / kg的剂量对雄性C57BL6小鼠进行IV和PO给药后,对生长因子受体(EGFR)进行了研究。

  2. 使用一系列快速UHPLC-MS和UHPLC-IM-HRMS方法(同时使用反相(RP)和亲水相互作用液相色谱(HILIC))研究了吉非替尼的药代动力学和代谢,以快速确定药物的药代动力学和代谢命运。

  3. 口服快速吸收导致大约1 h血浆血浆浓度达到峰值。7 µg / mL,其半衰期为3.8小时(静脉输液为2.6小时)下降,估计口服生物利用度为53%。吉非替尼本身是血浆提取物中主要的循环药物相关化合物,共鉴定出11种代谢物。

  4. 使用HILIC和RP-UPLC-IM-MS测得的尿谱分别检测了吉非替尼和10种代谢物或15种代谢物,包括检测多种新型葡糖醛酸苷结合物。

  5. 尽管在不到5分钟的时间内快速完成,但所采用的LC谱图分析方法对代谢物的覆盖率仍然很高,并且与以前的研究相比具有很好的对比性。

更新日期:2021-03-12
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