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 [13C,2H4]-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 (r2 > 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 talazoparib 在 ABCB1/ABCG2 缺陷小鼠中的药代动力学


开发了一种快速、灵敏、简单的 UHPLC-MS/MS 方法，用于测定小鼠血浆中 PARP 抑制剂 talazoparib，并使用 [13C，2H4]-talazoparib 作为内标 （IS） 进行了验证。分析程序包括使用单步脱蛋白从血浆中提取talazoparib和IS，并在ACQUITY UPLC RP18 HSS T3色谱柱上以0.4 mL/min的流速在5 min的运行时间内分离分析物。校准曲线在 0.5–100 ng/mL 的浓度范围内呈线性 （r2 > 0.99），并且可以准确定量 10 倍稀释的样品。talazoparib 的基质效应和平均提取回收率分别在 93.7-109% 和 87.7-105% 之间。质控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度。Talazoparib 在室温下表现出 6 小时的台式稳定性，在 4 °C 下自动进样和再注射稳定性至少 24 小时，并且在三个冻融循环后未观察到显着降解。开发的方法成功应用于涉及野生型小鼠和外排转运蛋白 ABCB1 （P-gp） 和 ABCG2 （BCRP） 遗传缺陷的动物口服 talazoparib 后连续采血的药代动力学研究。总之，我们的结果证明了成功开发了小鼠血浆中 talazoparib 的合适分析方法，并表明小鼠是评估涉及 talazoparib 治疗的转运蛋白介导的药物相互作用的有用模型。