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 50 mg/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 1 h of ca. 7 µg/mL, that declined with a half-life of 3.8 h (2.6 h 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 5 min, LC profiling methods being employed metabolite coverage was shown to be high and compared well with that of previous studies.

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。