Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population
Abstract Background 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 stud...
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doaj-befc15dd88aa40cd88b3ce61cb4ddd7a2020-11-24T20:47:59ZengBMCBMC Pharmacology and Toxicology2050-65112017-11-0118111010.1186/s40360-017-0178-xPharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese populationXueqing Li0Rutao Wang1Yang Liu2Yun Liu3Heng Zheng4Yabo Feng5Na Zhao6Hongbin Geng7Wanzhi Zhang8Aidong Wen9Department of Pharmacy, Xijing Hospital, Fourth Military Medical UniversityXi’an Libang Zhaoxin Biological Technology Co., LtdEliving Pharmaceutical Co., LtdXi’an Libang Zhaoxin Biological Technology Co., LtdDepartment of Pharmacy, Tongji HospitalEliving Pharmaceutical Co., LtdEliving Pharmaceutical Co., LtdXi’an Libang Zhaoxin Biological Technology Co., LtdXi’an Libang Zhaoxin Biological Technology Co., LtdDepartment of Pharmacy, Xijing Hospital, Fourth Military Medical UniversityAbstract Background 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. Methods 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. Results Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax 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 tmax 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. Conclusions 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 tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. Trial registration This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017).http://link.springer.com/article/10.1186/s40360-017-0178-xMetolazonePharmacokineticsFoodGenderTolerabilityClinical trial |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xueqing Li Rutao Wang Yang Liu Yun Liu Heng Zheng Yabo Feng Na Zhao Hongbin Geng Wanzhi Zhang Aidong Wen |
spellingShingle |
Xueqing Li Rutao Wang Yang Liu Yun Liu Heng Zheng Yabo Feng Na Zhao Hongbin Geng Wanzhi Zhang Aidong Wen Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population BMC Pharmacology and Toxicology Metolazone Pharmacokinetics Food Gender Tolerability Clinical trial |
author_facet |
Xueqing Li Rutao Wang Yang Liu Yun Liu Heng Zheng Yabo Feng Na Zhao Hongbin Geng Wanzhi Zhang Aidong Wen |
author_sort |
Xueqing Li |
title |
Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population |
title_short |
Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population |
title_full |
Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population |
title_fullStr |
Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population |
title_full_unstemmed |
Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population |
title_sort |
pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy chinese population |
publisher |
BMC |
series |
BMC Pharmacology and Toxicology |
issn |
2050-6511 |
publishDate |
2017-11-01 |
description |
Abstract Background 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. Methods 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. Results Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and Cmax 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 tmax 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. Conclusions 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 tmax of metolazone increased in the fed condition. Metolazone was well tolerated at the tested dose in this study. Trial registration This investigation is retrospectively registered at chictr.org.cn (ChiCTR-IIR-17012929, October 09 2017). |
topic |
Metolazone Pharmacokinetics Food Gender Tolerability Clinical trial |
url |
http://link.springer.com/article/10.1186/s40360-017-0178-x |
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