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Simultaneous Determination of Rivaroxaban and Enalapril in Rat Plasma by UPLC–MS/MS and Its Application to A Pharmacokinetic Interaction Study

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Abstract

Background and Objectives

There have been no animal experiments and clinical studies on the pharmacokinetic interaction between rivaroxaban and enalapril. To investigate whether a potential pharmacokinetic interaction is present between rivaroxaban and enalapril, a rapid and sensitive Ultra performance liquid chromatography—tandem mass spectrometry (UPLC–MS/MS) method was developed and validated to determine the concentration of rivaroxaban and enalapril in rat plasma and was then applied to a pharmacokinetic interaction study.

Methods

The analytes were separated on an Acquity UPLC BEH C18 chromatography column (2.1 × 50 mm, 1.7 μm) with acetonitrile and 0.1% formic acid as the mobile phase with gradient elution. The mass spectrometer was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of 436.1 → 145.1 m/z for rivaroxaban, 377.3 → 234.2 m/z for enalapril and 285.2 → 193.1 m/z for diazepam (IS).

Results

The method was validated over the concentration range of 1.0–200 ng/mL for rivaroxaban and 0.5–100 ng/mL for enalapril. The intra- and inter-day precision and accuracy of the quality control (QC) samples exhibited relative standard deviations (RSD) < 9.4% and the accuracy values ranged from − 8.3 to 9.6%. After co-administration of rivaroxaban and enalapril, the maximum plasma concentration (Cmax) and area under the systemic drug concentration–time curve from time 0 to infinity (AUC0–∞) of rivaroxaban were significantly increased by 19.6% (p < 0.05) and 21.3% (p < 0.05), respectively. On the contrary, the plasma clearance rate (CL/F) of rivaroxaban and enalapril was significantly decreased by 17.8% (p < 0.05) and 23.8% (p < 0.05), respectively.

Conclusions

The UPLC–MS/MS method was successfully applied to simultaneous determination of rivaroxaban and enalapril in rat plasma and applied to study the pharmacokinetic interaction between rivaroxaban and enalapril. The co-administration of rivaroxaban and enalapril resulted in a significant drug interaction in rats.

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Acknowledgements

The authors thank Guo-Xin Hu for providing DAS 2.0 software and his assistance and advice.

Author information

Author notes

  1. Shu Zheng, Shun-Bin Luo, Yi-Bin Mei these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Paediatric Surgery, The People’s Hospital of Lishui, Lishui, 323000, Zhejiang, China

    Shu Zheng

  2. Department of Clinical Pharmacy, The People’s Hospital of Lishui, Lishui, 323000, Zhejiang, China

    Shun-Bin Luo

  3. Department of Cardiology, The People’s Hospital of Lishui, Lishui, 323000, Zhejiang, China

    Yi-Bin Mei & Li-Jun Tong

  4. Department of Regional Medical Union, The People’s Hospital of Lishui, Lishui, 323000, Zhejiang, China

    Jing Guo

  5. Department of Clinical Laboratory, The People’s Hospital of Lishui, Lishui, Zhejiang, 323000, China

    Qiang Zhang

  6. Department of Neurosurgery, The People’s Hospital of Lishui, Lishui, 323000, Zhejiang, China

    Xia-Yan Ye

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  1. Shu Zheng
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Correspondence to Xia-Yan Ye.

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No source of funding was used in this study.

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None of the authors has any potential conflicts of interest to declare.

Ethical Approval

All experiments were approved by the Wenzhou Medical University Committee, and all of the experiments were performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Zheng, S., Luo, SB., Mei, YB. et al. Simultaneous Determination of Rivaroxaban and Enalapril in Rat Plasma by UPLC–MS/MS and Its Application to A Pharmacokinetic Interaction Study. Eur J Drug Metab Pharmacokinet 44, 229–236 (2019). https://doi.org/10.1007/s13318-018-0504-8

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