Foundation for Neglected Diseases Research, India.
Ayma Therapeutics Incorporated, USA.
J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jun 1;1174:122714. doi: 10.1016/j.jchromb.2021.122714. Epub 2021 Apr 20.
Triciribine (TCN) is a tricyclic nucleoside analog of adenosine and an inhibitor of Akt kinase. Triciribine 5'-monophosphate (TCNP) is a water-soluble analog of Triciribine and has progressed to Phase I and II clinical trials in oncology. TCNP is also an endogenous anabolite of TCN similar to other nucleoside phosphates. Clinical development of TCNP has been hampered by high pharmacokinetic variability due to complex interplay of TCN-TCNP conversion and reconversion in plasma, erythrocytes (RBC) and peripheral organs. TCN has been demonstrated to be an efficacious agent in mice models of acute lung injury at low doses (0.5 mg/kg/day) although its pharmacokinetic-pharmacodynamic (PK/PD) relationship remained unclear. We have developed and validated a sensitive, specific and robust LC/MS/MS assay for quantitation of TCN and TCNP in plasma and RBC. Using a simple protein precipitation method, quantitation of these analytes was accomplished with recoveries exceeding 85% and with a run time of 4 min. This assay was used to determine the pharmacokinetic parameters of TCN and TCNP in mice after single dose intravenous administration at 1, 3 and 10 mg/kg. TCNP accumulates in RBC, has low clearance and a half-life of 18 to 23 h. Unlike other nucleoside phosphates, TCNP was found to be relatively stable in mice plasma serving as a secondary depot. TCN levels were low and with high clearance relative to hepatic blood flow. A combination of sustained levels of TCNP in RBC and plasma serves as a depot for TCN to elicit robust therapeutic activity in acute lung injury mice models.
曲昔匹特（TCN）是一种腺嘌呤的三环核苷类似物，也是 Akt 激酶的抑制剂。曲昔匹特 5'-单磷酸酯（TCNP）是一种水溶性的 TCN 类似物，已在肿瘤学中进行到 I 期和 II 期临床试验。TCNP 也是 TCN 的内源性同化代谢物，与其他核苷磷酸盐相似。由于 TCN-TCNP 转化和再转化在血浆、红细胞（RBC）和外周器官中的复杂相互作用，导致 TCNP 的药代动力学变异性很高，从而阻碍了 TCNP 的临床开发。尽管 TCN 的药代动力学-药效学（PK/PD）关系仍不清楚，但 TCN 已被证明在低剂量（0.5mg/kg/天）的急性肺损伤小鼠模型中是一种有效的药物。我们已经开发并验证了一种灵敏、特异和稳健的 LC/MS/MS 测定法，用于定量测定血浆和 RBC 中的 TCN 和 TCNP。使用简单的蛋白沉淀法，这些分析物的定量回收率超过 85%，运行时间为 4 分钟。该测定法用于在 1、3 和 10mg/kg 单次静脉给药后测定小鼠 TCN 和 TCNP 的药代动力学参数。TCNP 在 RBC 中积累，清除率低，半衰期为 18 至 23 小时。与其他核苷磷酸盐不同，TCNP 在小鼠血浆中相对稳定，可作为次级储存库。与肝血流量相比，TCN 水平较低，清除率较高。TCNP 在 RBC 和血浆中的持续水平结合作为 TCN 的储存库，可在急性肺损伤小鼠模型中引起强大的治疗活性。
