Zhou Jiezhao, Chen Meiling, Li Ying, Yu Fanglin, Cheng Xiaohui, Yang Yang, Liu Yan, Xie Xiangyang, Li Zhiping, Zhang Hui, Mei Xingguo
1 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
2 Department of pharmacokinetics, Hunan Research Center for Safety Evaluation of Drugs, Changsha, China.
Eur J Mass Spectrom (Chichester). 2017 Oct;23(5):305-312. doi: 10.1177/1469066717716726. Epub 2017 Jul 10.
Combination of metolazone (0.5 mg) and valsartan (80 mg) has been verified as a promising therapy treatment for hypertension. In order to facilitate to pharmacokinetic research, it needs a method for the simultaneously determination of metolazone and valsartan in biological samples. However, there are no relative reports so far. In order to facilitate to pharmacokinetic research, an on-line solid phase extraction coupled with liquid chromatography-tandem mass spectrometry method for the simultaneous determination of metolazone and valsartan in beagle dog plasma was developed and validated in this study. An on-line solid phase extraction column Retain PEP Javelin (10 mm × 2.1 mm) was used to remove impurities in plasma samples. The metolazone, valsartan and internal standard (losartan) were separated on a Poroshell 120 SB-C18 column (4.6 mm × 50 mm × 2.7 µm) with a gradient elution procedure. Acidified acetonitrile/water mixture was used as a mobile phase. The selected multiple-reaction monitoring mode in positive ion was performed and the parent to the product transitions m/z 366/259, m/z 436.2/291 and m/z 423.4/207 were used to measure the metolazone, valsartan and losartan. The method was linear over the range of 0.1-100 ng/mL and 1-1000 ng/mL for metolazone and valsartan, respectively. This method was validated in terms of specificity, linearity, sensitivity, precision, accuracy, matrix effect, and stability and then successfully applied to pharmacokinetic studies of the metolazone and valsartan combination tablets in beagle dogs.
美托拉宗（0.5毫克）和缬沙坦（80毫克）联合用药已被证实是一种有前景的高血压治疗方法。为便于进行药代动力学研究，需要一种同时测定生物样品中美托拉宗和缬沙坦的方法。然而，目前尚无相关报道。为便于进行药代动力学研究，本研究建立并验证了一种在线固相萃取-液相色谱-串联质谱法，用于同时测定比格犬血浆中的美托拉宗和缬沙坦。使用在线固相萃取柱Retain PEP Javelin（10毫米×2.1毫米）去除血浆样品中的杂质。美托拉宗、缬沙坦和内标（氯沙坦）在Poroshell 120 SB-C18柱（4.6毫米×50毫米×2.7微米）上通过梯度洗脱程序进行分离。酸化乙腈/水混合物用作流动相。采用正离子模式下的选择多反应监测模式，以m/z 366/259、m/z 436.2/291和m/z 423.4/207的母离子到子离子转换来测定美托拉宗、缬沙坦和氯沙坦。该方法在美托拉宗浓度为0.1 - 100纳克/毫升、缬沙坦浓度为1 - 1000纳克/毫升范围内呈线性。该方法在特异性、线性、灵敏度、精密度、准确度、基质效应和稳定性方面得到验证，然后成功应用于比格犬中美托拉宗和缬沙坦复方片剂的药代动力学研究。
