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Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Human in vitro and dog in vitro/in vivo researches indicate that the drug–drug interaction (DDI) of decreased plasma valproic acid (VPA) concentration by co-administration of carbapenem antibiotics is caused by inhibition of acylpeptide hydrolase (APEH)-mediated VPA acylglucuronide (VPA-G) hydrolysis by carbapenems. In this study, we investigated VPA disposition and APEH activities in TK-NOG chimeric mice, whose livers were highly replaced with human hepatocytes, to evaluate the utility of this animal model and the clinical relevance of the DDI mechanism.

Methods

VPA and VPA-G concentrations in plasma, urinary excretion of VPA-G and APEH activity in humanized livers were measured after co-administration of VPA with meropenem (MEPM) to chimeric mice.

Results

After co-administration with MEPM to the chimeric mice, plasma VPA concentration more rapidly decreased than without the co-administration. An increase in plasma AUC and urinary excretion of VPA-G was also observed. APEH activity in humanized livers was strongly inhibited even at 24 h after co-administration of MEPM to the chimeric mice.

Conclusion

The DDI of VPA with carbapenems was successfully observed in chimeric mice with humanized livers. The DDI was caused by long-lasting inhibition of hepatic APEH-mediated VPA-G hydrolysis by carbapenems, which strongly supports the APEH-mediated mechanism of the clinical DDI. This is the first example showing the usefulness of chimeric mice with humanized livers for evaluation of a DDI via non-cytochrome P450 enzyme.

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Acknowledgements

We gratefully acknowledge Toshihiko Namba for the expert help with the animal experimental environment.

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Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa-Ku, Tokyo, 140-8710, Japan

    Eiko Suzuki, Kumiko Koyama, Daisuke Nakai, Ryoya Goda & Hiroshi Kuga

  2. Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

    Kan Chiba

Authors
  1. Eiko Suzuki
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  2. Kumiko Koyama
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  3. Daisuke Nakai
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  4. Ryoya Goda
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  5. Hiroshi Kuga
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  6. Kan Chiba
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Corresponding author

Correspondence to Eiko Suzuki.

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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Ethical approval

All procedures performed in studies involving animals were in accordance with the ethical standards of practices of the institutions at which the studies were conducted.

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Suzuki, E., Koyama, K., Nakai, D. et al. Observation of Clinically Relevant Drug Interaction in Chimeric Mice with Humanized Livers: The Case of Valproic Acid and Carbapenem Antibiotics. Eur J Drug Metab Pharmacokinet 42, 965–972 (2017). https://doi.org/10.1007/s13318-017-0413-2

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  • DOI: https://doi.org/10.1007/s13318-017-0413-2

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