Li Xueqing, Wang Rutao, Liu Yang, Liu Yun, Zheng Heng, Feng Yabo, Zhao Na, Geng Hongbin, Zhang Wanzhi, Wen Aidong
Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Xi'an Libang Zhaoxin Biological Technology Co., Ltd, Xi'an, China.
BMC Pharmacol Toxicol. 2017 Nov 16;18(1):73. doi: 10.1186/s40360-017-0178-x.
Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters.
An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams.
Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t of metolazone was increased by approximately 100% in the fed condition. Metolazone was well tolerated at the tested dose, and no adverse effects were observed.
Single dosing with 0.5 mg, 1 mg, or 2 mg metolazone yielded linear plasma pharmacokinetic properties in healthy Chinese subjects. Multiple oral doses of metolazone did not display significantly different distributions or elimination characteristics from those observed for a single dose. Gender factors did not appear to influence the pharmacokinetic parameter variation of metolazone. The t of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study.
This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).
美托拉宗是一种来自喹唑啉类的利尿、促尿钠排泄和抗高血压化合物，具有与其他噻嗪类利尿药相似的药用特性。然而，美托拉宗在中国人群中的药代动力学鲜有研究。本研究旨在考察健康中国受试者口服单剂量和多剂量美托拉宗后的药代动力学特征、安全性特征和耐受性，以及食物和性别对口服美托拉宗药代动力学参数的影响。
在健康中国受试者中进行了一项开放标签、随机、单剂量和多剂量给药的研究。该研究包括3个研究组：0.5毫克、1毫克和2毫克剂量组是第一阶段的单剂量研究组。符合条件的志愿者被随机口服一片0.5毫克、1毫克或2毫克的美托拉宗片剂。0.5毫克剂量组也是多剂量研究组的一部分，1毫克剂量组是第二阶段的食物效应研究组。在给药前和给药后长达48小时采集人体血浆样本。采用经过验证的液相色谱串联质谱法对美托拉宗的人体血浆样本浓度进行定量。使用WinNonlin 6.4版通过非房室分析方法计算药代动力学数据。根据不良事件、体格检查、12导联心电图和其他临床实验室检查评估耐受性。
30名符合条件的受试者（15名男性和15名女性）登记参加了我们的研究并完成了所有研究阶段。根据线性回归分析，单剂量给药后AUC和C呈现剂量比例关系。药代动力学数据比较显示，男性组和女性组之间的差异无统计学意义。在进食条件下，美托拉宗t增加约100%。美托拉宗在测试剂量下耐受性良好，未观察到不良反应。
在健康中国受试者中，0.5毫克、1毫克或2毫克美托拉宗单剂量给药产生线性血浆药代动力学特性。多次口服美托拉宗与单剂量相比，分布或消除特征无显著差异。性别因素似乎不影响美托拉宗药代动力学参数的变化。在进食条件下，美托拉宗t增加。在本研究中，美托拉宗在测试剂量下耐受性良好。
本研究已在chictr.org.cn进行回顾性注册（ChiCTR-IIR-17012929，2017年10月9日）。
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