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Quantitative Analysis of Daporinad (FK866) and Its In Vitro and In Vivo Metabolite Identification Using Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry
Molecules ( IF 4.2 ) Pub Date : 2022-03-21 , DOI: 10.3390/molecules27062011 Minjae Park 1 , Byeong Ill Lee 1 , Jangmi Choi 1 , Yuri Park 1 , Seo-Jin Park 1 , Jeong-Hyeon Lim 1 , Jiyu Lee 1 , Young G Shin 1
Molecules ( IF 4.2 ) Pub Date : 2022-03-21 , DOI: 10.3390/molecules27062011 Minjae Park 1 , Byeong Ill Lee 1 , Jangmi Choi 1 , Yuri Park 1 , Seo-Jin Park 1 , Jeong-Hyeon Lim 1 , Jiyu Lee 1 , Young G Shin 1
Affiliation
Daporinad (FK866) is one of the highly specific inhibitors of nicotinamide phosphoribosyl transferase (NAMPT) and known to have its unique mechanism of action that induces the tumor cell apoptosis. In this study, a simple and sensitive liquid chromatography–quadrupole-time-of-flight–mass spectrometric (LC-qTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (DMPK) properties of Daporinad in mice. A simple protein precipitation method using acetonitrile (ACN) was used for the sample preparation and the pre-treated samples were separated by a C18 column. The calibration curve was evaluated in the range of 1.02~2220 ng/mL and the quadratic regression (weighted 1/concentration2) was used for the best fit of the curve with a correlation coefficient ≥ 0.99. The qualification run met the acceptance criteria of ±25% accuracy and precision values for QC samples. The dilution integrity was verified for 5, 10 and 30-fold dilution and the accuracy and precision of the dilution QC samples were also satisfactory within ±25% of the nominal values. The stability results indicated that Daporinad was stable for the following conditions: short-term (4 h), long-term (2 weeks), freeze/thaw (three cycles). This qualified method was successfully applied to intravenous (IV) pharmacokinetic (PK) studies of Daporinad in mice at doses of 5, 10 and 30 mg/kg. As a result, it showed a linear PK tendency in the dose range from 5 to 10 mg/kg, but a non-linear PK tendency in the dose of 30 mg/kg. In addition, in vitro and in vivo metabolite identification (Met ID) studies were conducted to understand the PK properties of Daporinad and the results showed that a total of 25 metabolites were identified as ten different types of metabolism in our experimental conditions. In conclusion, the LC-qTOF-MS assay was successfully developed for the quantification of Daporinad in mouse plasma as well as for its in vitro and in vivo metabolite identification.
中文翻译:
使用液相色谱-四极杆-飞行时间质谱法定量分析 Daporinad (FK866) 及其体外和体内代谢物鉴定
Daporinad (FK866) 是烟酰胺磷酸核糖基转移酶 (NAMPT) 的高度特异性抑制剂之一,已知其具有诱导肿瘤细胞凋亡的独特作用机制。在这项研究中,开发了一种简单而灵敏的液相色谱-四极杆飞行时间质谱 (LC-qTOF-MS) 测定法,用于评估 Daporinad 在小鼠中的药物代谢和药代动力学 (DMPK) 特性。使用乙腈 (ACN) 的简单蛋白质沉淀法用于样品制备,预处理的样品通过 C18 柱分离。校准曲线在 1.02~2220 ng/mL 和二次回归(加权 1/浓度2) 用于曲线的最佳拟合,相关系数≥0.99。鉴定运行符合 QC 样品的 ±25% 准确度和精密度值的验收标准。对 5、10 和 30 倍稀释度验证了稀释完整性,稀释 QC 样品的准确度和精密度在标称值的 ±25% 范围内也令人满意。稳定性结果表明,Daporinad 在以下条件下是稳定的:短期(4 小时)、长期(2 周)、冻融(三个循环)。这种合格的方法成功地应用于小鼠中 Daporinad 的静脉内 (IV) 药代动力学 (PK) 研究,剂量为 5、10 和 30 mg/kg。结果,在5~10mg/kg的剂量范围内呈线性PK趋势,而在30mg/kg剂量范围内呈非线性PK趋势。此外,进行了体外和体内代谢物鉴定 (Met ID) 研究以了解 Daporinad 的 PK 特性,结果表明,在我们的实验条件下,共有 25 种代谢物被鉴定为 10 种不同类型的代谢。总之,LC-qTOF-MS 测定已成功开发用于定量小鼠血浆中的 Daporinad 及其体外和体内代谢物鉴定。
更新日期:2022-03-21
中文翻译:
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使用液相色谱-四极杆-飞行时间质谱法定量分析 Daporinad (FK866) 及其体外和体内代谢物鉴定
Daporinad (FK866) 是烟酰胺磷酸核糖基转移酶 (NAMPT) 的高度特异性抑制剂之一,已知其具有诱导肿瘤细胞凋亡的独特作用机制。在这项研究中,开发了一种简单而灵敏的液相色谱-四极杆飞行时间质谱 (LC-qTOF-MS) 测定法,用于评估 Daporinad 在小鼠中的药物代谢和药代动力学 (DMPK) 特性。使用乙腈 (ACN) 的简单蛋白质沉淀法用于样品制备,预处理的样品通过 C18 柱分离。校准曲线在 1.02~2220 ng/mL 和二次回归(加权 1/浓度2) 用于曲线的最佳拟合,相关系数≥0.99。鉴定运行符合 QC 样品的 ±25% 准确度和精密度值的验收标准。对 5、10 和 30 倍稀释度验证了稀释完整性,稀释 QC 样品的准确度和精密度在标称值的 ±25% 范围内也令人满意。稳定性结果表明,Daporinad 在以下条件下是稳定的:短期(4 小时)、长期(2 周)、冻融(三个循环)。这种合格的方法成功地应用于小鼠中 Daporinad 的静脉内 (IV) 药代动力学 (PK) 研究,剂量为 5、10 和 30 mg/kg。结果,在5~10mg/kg的剂量范围内呈线性PK趋势,而在30mg/kg剂量范围内呈非线性PK趋势。此外,进行了体外和体内代谢物鉴定 (Met ID) 研究以了解 Daporinad 的 PK 特性,结果表明,在我们的实验条件下,共有 25 种代谢物被鉴定为 10 种不同类型的代谢。总之,LC-qTOF-MS 测定已成功开发用于定量小鼠血浆中的 Daporinad 及其体外和体内代谢物鉴定。