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Development of a simultaneous LC–MS/MS method to predict in vivo drug–drug interaction in mice

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A Correction to this article was published on 13 November 2018

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Abstract

Cocktail substrates are useful in investigating drug–drug interactions (DDI) that can rapidly identify the cytochrome P450 (CYP) isoforms that interact with test drugs. In this study, we developed and validated five probe drugs for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A using LC–MS/MS to determine CYP activities in mice. The five probe substrates were caffeine (2 mg/kg), bupropion (30 mg/kg), omeprazole (4 mg/kg), dextromethorphan (40 mg/kg), and midazolam (2 mg/kg) for CYP1A, CYP2B, CYP2C, CYP2D, and CYP3A, respectively. The cocktail substrates were orally administered to male 5-week-old ICR mice over 0–240 min. The analytical method was validated; it showed high selectivity, linearity, and acceptable accuracy. We confirmed the lack of interaction of this cocktail in the control state (no effect of CYP inducer or inhibitor) and suggested AUCratio (metabolite/substrate) as a unit to evaluate DDI in vivo. In addition, the cocktail assay was applied for the determination of pharmacokinetic parameters against phenobarbital as a selective CYP2B inducer and ketoconazole as a strong CYP3A inhibitor. The concentration of cocktail substrates and the LC–MS/MS method were optimized. In conclusion, we developed a simultaneous and comprehensive analysis system for predicting potential DDI in mice.

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Change history

  • 13 November 2018

    The author would like to change conflict of interest statement of the online published article.

  • 13 November 2018

    The author would like to change conflict of interest statement of the online published article.

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Acknowledgements

This work was supported by the Korea Institute of Planning and Evaluation for Technology in Food, Agriculture, Forestry and Fisheries (IPET) through the Export Promotion Technology Development Program, fund from the Ministry of Agriculture, Food and Rural Affairs (MAFRA) (Grant Number 316017-3), and by the National Research Foundation (NRF) Grant funded by the Korean government (MSIP) (2015R1A2A2A01004286).

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Authors and Affiliations

  1. BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea

    Jung Jae Jo, Jun Hyun Jo, SunJoo Kim & Sangkyu Lee

  2. Department of Periodontology, School of Dentistry, Kyungpook National University, 2177 Dalgubeol-daero, Jung-gu, Daegu, 41940, Republic of Korea

    Jae-Mok Lee

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  1. Jung Jae Jo
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  2. Jun Hyun Jo
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Correspondence to Jae-Mok Lee or Sangkyu Lee.

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Jo, J.J., Jo, J.H., Kim, S. et al. Development of a simultaneous LC–MS/MS method to predict in vivo drug–drug interaction in mice. Arch. Pharm. Res. 41, 450–458 (2018). https://doi.org/10.1007/s12272-018-1012-8

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  • DOI: https://doi.org/10.1007/s12272-018-1012-8

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