A rapid, sensitive, and simple UHPLC-MS/MS method for the determination of the PARP inhibitor talazoparib in mouse plasma was developed and validated using [C,H]-talazoparib as an internal standard (IS). The assay procedure involved extraction of talazoparib and the IS from plasma using a single-step deproteination and separation of the analytes was achieved on an ACQUITY UPLC RP18 HSS T3 column with a mobile phase gradient at a flow rate of 0.4 mL/min in a run time of 5 min. The calibration curve was linear ( > 0.99) over the concentration range of 0.5–100 ng/mL, and 10-fold dilution of samples could be accurately quantitated. The matrix effect and mean extraction recovery for talazoparib were between 93.7-109% and 87.7–105%, respectively. Precision and percent bias of quality control samples were always less than ±15%, indicating reproducibility and accuracy of the method. Talazoparib demonstrated bench-top stability at room temperature for 6 h, auto-sampler and reinjection stability at 4 °C for at least 24 h, and no significant degradation was observed after three freeze-thaw cycles. The developed method was successfully applied to pharmacokinetic studies involving serial blood sampling after oral administration of talazoparib to wild-type mice and animals with a genetic deficiency of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Together, our results demonstrate the successful development of a suitable analytical method for talazoparib in mouse plasma and suggest that mice are a useful model to evaluate transporter-mediated drug-drug interactions involving therapy with talazoparib.

中文翻译：

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使用新型 UHPLC-MS/MS 方法探索他拉佐帕尼在 ABCB1/ABCG2 缺陷小鼠中的药代动力学

开发了一种快速、灵敏且简单的 UHPLC-MS/MS 方法，用于测定小鼠血浆中的 PARP 抑制剂他佐帕尼，并使用 [C,H]-他佐帕尼作为内标 (IS) 进行验证。检测程序包括使用单步脱蛋白从血浆中提取他拉佐帕尼和内标，并在 ACQUITY UPLC RP18 HSS T3 色谱柱上以 0.4 mL/min 的流速运行流动相梯度来实现分析物的分离时间5分钟。校准曲线在0.5-100 ng/mL的浓度范围内呈线性（>0.99），并且可以准确定量样品的10倍稀释。他拉佐帕尼的基质效应和平均提取回收率分别为 93.7-109% 和 87.7-105%。质量控制样品的精密度和百分比偏差始终小于±15%，表明该方法的重现性和准确性。 Talazoparib 在室温下表现出 6 小时的台式稳定性，在 4 °C 下自动进样器和回注稳定性至少 24 小时，并且在三个冻融循环后没有观察到明显的降解。所开发的方法成功应用于药代动力学研究，包括对野生型小鼠和具有外排转运蛋白 ABCB1 (P-gp) 和 ABCG2 (BCRP) 遗传缺陷的动物口服他拉佐帕尼后进行连续血液采样。总之，我们的结果证明成功开发了一种适用于小鼠血浆中他佐帕尼的分析方法，并表明小鼠是评估涉及他佐帕尼治疗的转运蛋白介导的药物相互作用的有用模型。