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Pharmacokinetic Study of Conjugated Equine Estrogens in Healthy Chinese Postmenopausal Women Using a Parallel Two-Column LC–MS/MS Method

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Abstract

Background and Objective

Postmenopausal women often require estrogen supplementation to improve menopausal and postmenopausal vasomotor symptoms and maintain hormonal balance. Conjugated equine estrogens extracted from the urine of pregnant mares are commonly used to provide this estrogen replacement therapy. The complex composition of this mixture of animal sulfated metabolites makes its bioanalysis challenging such that its detailed pharmacokinetics has not been fully characterized. The purpose of this work is to reveal the pharmacokinetic behavior of conjugated equine estrogens in healthy Chinese postmenopausal women by a parallel two-column LC–MS/MS method.

Methods

An open-label study was carried out in 35 Chinese healthy postmenopausal women who received a single dose of Premarin® 0.625 mg. A high-throughput column-switching liquid chromatography-tandem mass spectrometry method was developed to determine four conjugated estrogens and two unconjugated estrogens formed by hydrolysis in vivo. The method multiplexes two high-performance liquid chromatography systems into one mass spectrometer and incorporates the positive/negative ion switching acquisition mode of mass spectrometry to significantly increase analysis efficiency. Pharmacokinetics was determined using non-compartmental methods.

Results

Both conjugated and unconjugated estrogens can be analyzed simultaneously in a single run with an analysis time of 13.0 minutes in the column-switching liquid chromatography-tandem mass spectrometry method as opposed to 23.0 minutes in a single-column liquid chromatography-tandem mass spectrometry system. The exposures (maximum concentration and area under the curve) of estrone and equilin in Chinese women were higher than those in the North American women.

Conclusions

The fully validated assay was successfully applied to a pharmacokinetic study in healthy postmenopausal Chinese women after oral administration of a conjugated equine estrogen tablet. This study suggests that Chinese postmenopausal women achieve the same level of unconjugated estrogens in plasma at a lower dose of conjugated equine estrogens than North American women.

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Author notes

  1. Meiyun Shi and Lei Yin contributed equally to this work.

Authors and Affiliations

  1. Research Center for Drug Metabolism, School of Life Science, Jilin University, 2699 Qianjin Street, Changchun, 130012, People’s Republic of China

    Meiyun Shi, Lei Yin, Can Wang, Lanlan Cai, Tinglan Zhang, Xiaotong Zhou, J. Paul Fawcett & Jingkai Gu

  2. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, People’s Republic of China

    Meiyun Shi & Lei Yin

  3. School of Pharmaceutical Sciences, Jilin University, Changchun, People’s Republic of China

    Yantong Sun

  4. College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, People’s Republic of China

    Xiaoli Gao

  5. Xinjiang Key Laboratory of Active Components and Drug Release Technology of Natural Drugs, Urumqi, People’s Republic of China

    Xiaoli Gao

  6. Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Ministry of Education, Beijing, People’s Republic of China

    Xiaoli Gao

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  1. Meiyun Shi
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Corresponding authors

Correspondence to Xiaoli Gao or Jingkai Gu.

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Funding

This research was supported by the National Natural Science Foundation of China (Grant numbers 81703607, 81430087, 81603182, 81673396), the Fundamental Research Fund for the Central Universities (Grant numbers DUT21RC(3)057, DUT18LK24, DUT20RC(4)012), the Doctoral Scientific Research Foundation of Liaoning Province (20170520115), and Major National Science and Technology of China (2017ZX09101001).

Conflicts of interest/competing interests

Meiyun Shi, Lei Yin, Yantong Sun, Can Wang, Lanlan Cai, Tinglan Zhang, Xiaotong Zhou, J. Paul Fawcett, Xiaoli Gao and Jingkai Gu have no conflicts of interest that are directly relevant to the content of this article.

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The study was approved by the Ethics Committee of the Second Clinical Hospital affiliated to Chinese Medical University, Shenyang, China.

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Shi, M., Yin, L., Sun, Y. et al. Pharmacokinetic Study of Conjugated Equine Estrogens in Healthy Chinese Postmenopausal Women Using a Parallel Two-Column LC–MS/MS Method. Clin Pharmacokinet 61, 1571–1583 (2022). https://doi.org/10.1007/s40262-022-01177-4

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