Gi Ju Lee, Jin Woo Kim, Hae-In Choi, Jin Young Choi, Kwan Hyung Cho, Tae-Sung Koo
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Optimal chromatographic separation in terms of peak intensity and symmetry was acquired using a 4-µm Polar-RP 80 Å (2.0 × 150 mm) column with ammonium acetate (5 mM) in distilled water–acetonitrile (50:50, v/v). The retention times of AZD5305 and internal standard (IS; olaparib) were 1.82 min and 1.99 min, respectively. Detection was carried out via triple quadrupole mass spectrometry in positive ion mode employing multiple reaction monitoring transitions at m / z 407.0 → 376.0 for AZD5305 and m / z 435.0 → 281.2 for the IS. The LC–MS/MS method was linear in the range 1–1000 ng/mL with a correlation coefficient ≥ 0.990 and showed acceptable values of major parameters including accuracy, precision, and recovery. Additionally, AZD5305 showed high stability under various conditions. The in vivo and in vitro pharmacokinetics of AZD5305 were successfully characterized by employing the validated LC–MS/MS method. A high level of drug exposure and linear pharmacokinetics were observed after intravenous (IV) bolus and oral administration (PO) of AZD5305 at 0.1–1 mg/kg and 0.1–3 mg/kg, respectively. The bioavailability was close to 100%, and the metabolic stability of AZD5305 in hepatic microsomes of mice and humans was very high. 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AZD5305, a selective PARP1 inhibitor currently in Phase 1/2 clinical trials, may avoid the side effects caused by PARP2. However, the in vivo pharmacokinetic characteristics of AZD5305 and its bioanalytical methods are unknown. Therefore, a method based on liquid chromatography with tandem mass spectroscopy (LC–MS/MS) was developed and validated to quantify AZD5305 in plasma of mice. Optimal chromatographic separation in terms of peak intensity and symmetry was acquired using a 4-µm Polar-RP 80 Å (2.0 × 150 mm) column with ammonium acetate (5 mM) in distilled water–acetonitrile (50:50, v/v). The retention times of AZD5305 and internal standard (IS; olaparib) were 1.82 min and 1.99 min, respectively. Detection was carried out via triple quadrupole mass spectrometry in positive ion mode employing multiple reaction monitoring transitions at m / z 407.0 → 376.0 for AZD5305 and m / z 435.0 → 281.2 for the IS. 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引用次数: 0
摘要
摘要聚(adp -核糖)聚合酶(PARP)抑制剂对乳腺癌易感基因(BRCA)突变的卵巢癌和乳腺癌有效,但存在不良副作用,如血液毒性。AZD5305是一种选择性PARP1抑制剂,目前正在进行1/2期临床试验,可以避免PARP2引起的副作用。然而,AZD5305的体内药代动力学特性及其生物分析方法尚不清楚。为此,建立了液相色谱-串联质谱(LC-MS /MS)定量小鼠血浆中AZD5305的方法,并进行了验证。采用4µm Polar-RP 80 Å (2.0 × 150 mm)柱,乙酸铵(5 mm),蒸馏水-乙腈(50:50,v/v),获得了峰强度和对称性最佳的色谱分离。AZD5305与内标(IS)的保留时间;奥拉帕尼)分别为1.82 min和1.99 min。AZD5305在m / z 407.0→376.0和IS在m / z 435.0→281.2的多重反应监测跃迁下,采用正离子模式进行三重四极杆质谱检测。LC-MS /MS方法在1 ~ 1000 ng/mL范围内呈良好的线性关系,相关系数≥0.990,准确度、精密度、回收率均为可接受值。此外,AZD5305在各种条件下都表现出很高的稳定性。采用验证的LC-MS /MS方法对AZD5305的体内和体外药动学进行了表征。AZD5305静脉(IV)和口服(PO)剂量分别为0.1-1 mg/kg和0.1-3 mg/kg后,呈高水平的药物暴露和线性药代动力学。生物利用度接近100%,AZD5305在小鼠和人肝微粒体中的代谢稳定性非常高。这些结果可能有助于改善用于治疗源自BRCA突变的恶性肿瘤的PARP抑制剂。
Liquid chromatography-tandem mass spectrometry for pharmacokinetics evaluation of AZD5305, a selective PARP1 inhibitor, in mice
Abstract Poly (ADP-ribose) polymerase (PARP) inhibitors that are effective against ovarian and breast cancers with breast cancer susceptibility gene (BRCA) mutations have undesirable side effects, such as hematological toxicity. AZD5305, a selective PARP1 inhibitor currently in Phase 1/2 clinical trials, may avoid the side effects caused by PARP2. However, the in vivo pharmacokinetic characteristics of AZD5305 and its bioanalytical methods are unknown. Therefore, a method based on liquid chromatography with tandem mass spectroscopy (LC–MS/MS) was developed and validated to quantify AZD5305 in plasma of mice. Optimal chromatographic separation in terms of peak intensity and symmetry was acquired using a 4-µm Polar-RP 80 Å (2.0 × 150 mm) column with ammonium acetate (5 mM) in distilled water–acetonitrile (50:50, v/v). The retention times of AZD5305 and internal standard (IS; olaparib) were 1.82 min and 1.99 min, respectively. Detection was carried out via triple quadrupole mass spectrometry in positive ion mode employing multiple reaction monitoring transitions at m / z 407.0 → 376.0 for AZD5305 and m / z 435.0 → 281.2 for the IS. The LC–MS/MS method was linear in the range 1–1000 ng/mL with a correlation coefficient ≥ 0.990 and showed acceptable values of major parameters including accuracy, precision, and recovery. Additionally, AZD5305 showed high stability under various conditions. The in vivo and in vitro pharmacokinetics of AZD5305 were successfully characterized by employing the validated LC–MS/MS method. A high level of drug exposure and linear pharmacokinetics were observed after intravenous (IV) bolus and oral administration (PO) of AZD5305 at 0.1–1 mg/kg and 0.1–3 mg/kg, respectively. The bioavailability was close to 100%, and the metabolic stability of AZD5305 in hepatic microsomes of mice and humans was very high. These results may contribute to the improvement of PARP inhibitors that are used to treat malignancies originating from BRCA mutations.
期刊介绍:
The Journal of Analytical Science and Technology (JAST) is a fully open access peer-reviewed scientific journal published under the brand SpringerOpen. JAST was launched by Korea Basic Science Institute in 2010. JAST publishes original research and review articles on all aspects of analytical principles, techniques, methods, procedures, and equipment. JAST’s vision is to be an internationally influential and widely read analytical science journal. Our mission is to inform and stimulate researchers to make significant professional achievements in science. We aim to provide scientists, researchers, and students worldwide with unlimited access to the latest advances of the analytical sciences.