Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Feb 15;917-918:62-70. doi: 10.1016/j.jchromb.2012.12.025. Epub 2013 Jan 9.
Ureidomustin hydrochloride (BO-1055) was designed as a water-soluble nitrogen-mustard, which exhibited potent anticancer activity and was selected as a candidate for preclinical studies. However, up to date, there is rarely an easy and economic method to quantize ureidomustin in the biological samples. The aim of this study is to develop a simple yet valid quantization method to tackle this challenge. Here we present a combined high-performance liquid chromatography with photodiode array (HPLC-PDA) method in quantizing the ureidomustin in the plasma and various organs of Sprague-Dawley rats. The method was validated in terms of precision, accuracy, and extraction recovery. Furthermore, the established method was applied to study pharmacokinetics of ureidomustin in the rat's plasma and verified via a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Calibration curves of the plasma and organ samples were falling at the range between 0.5-50μg/mL and 0.1-50μg/mL (r(2)≥0.999 and CV≤±15%), respectively. The limits of detection (LOD) were 0.1μg/mL for plasma samples and 0.05μg/mL for organ samples, while the detection limits of quantification (LOQ) were 0.5μg/mL for plasma samples and 0.1μg/mL for organ samples. The average recovery of ureidomustin was about 83%. These results demonstrated a linear pharmacokinetic pattern at dosages of 10 and 30mg/kg. The pharmacokinetic data revealed that ureidomustin was best fitted to a two-compartment model with a rapid distribution phase and a slow elimination phase. Besides, after a short intravenous administration time at the dose of 10mg/kg, ureidomustin was found to be quickly distributed to all organs in rats, accumulated mainly in the kidney, and only a limited amount was detected in the brain.
盐酸脲嘧啶氮芥 (BO-1055) 被设计为一种水溶性氮芥，具有很强的抗癌活性，被选为临床前研究的候选药物。然而，迄今为止，很少有一种简单且经济的方法可以对生物样品中的脲嘧啶氮芥进行定量。本研究旨在开发一种简单而有效的定量方法来解决这一挑战。在这里，我们提出了一种结合高效液相色谱与光电二极管阵列 (HPLC-PDA) 的方法，用于定量检测 Sprague-Dawley 大鼠血浆和各种器官中的脲嘧啶氮芥。该方法在精密度、准确性和提取回收率方面进行了验证。此外，该方法还应用于研究大鼠血浆中脲嘧啶氮芥的药代动力学，并通过液相色谱串联质谱 (LC-MS/MS) 方法进行验证。血浆和器官样品的校准曲线在 0.5-50μg/mL 和 0.1-50μg/mL 范围内（r(2)≥0.999，CV≤±15%）。血浆样品的检测限 (LOD) 为 0.1μg/mL，器官样品的检测限 (LOD) 为 0.05μg/mL，定量下限 (LOQ) 分别为 0.5μg/mL 和 0.1μg/mL。脲嘧啶氮芥的平均回收率约为 83%。这些结果表明，在 10 和 30mg/kg 剂量下，脲嘧啶氮芥呈线性药代动力学模式。药代动力学数据表明，脲嘧啶氮芥最好符合两室模型，具有快速分布相和缓慢消除相。此外，在 10mg/kg 的静脉注射时间较短后，发现脲嘧啶氮芥迅速分布到大鼠的所有器官中，主要在肾脏中积累，而在大脑中仅检测到有限量。
