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Evaluation of the Utility of Chimeric Mice with Humanized Livers for the Characterization and Profiling of the Metabolites of a Selective Inhibitor (YM543) of the Sodium-Glucose Cotransporter 2

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Abstract

Purpose

YM543 is a novel selective inhibitor of the sodium-glucose cotransporter 2. The objectives of the current study were to evaluate the utility of mice with humanized livers to predict human drug metabolites using YM543 as a case example.

Methods

Metabolites of YM543 generated in humans and experimental animals including chimeric mice with humanized liver, PXB mice, were analyzed via liquid chromatography-mass spectrometry, liquid chromatography-radiometric detector or nuclear magnetic resonance spectrometer.

Results

After oral administration of YM543, metabolites M1–M5 were detected in human plasma and urine. M2–M4 were detected in at least one species while M1 was not generated by experimental animals or in vitro systems. In the metabolite profiling in PXB mice, M1 was detected in both plasma and urine samples.

Conclusions

Metabolite profile of YM543 in PXB mice and humans was closely resemble. and the human specific metabolite was detected in the model mice. The human specific metabolite, M1, was difficult to know in advance to clinical study. The ability to predict the human metabolite profile including presence of human specific metabolites using PXB mice will likely facilitate development of new drug candidates for human use.

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Abbreviations

COSY:

Correlation spectroscopy

CYP:

Cytochrome P450

HMBC:

Heteronuclear multiple bond correlation

HPLC:

High-performance liquid chromatography

HSQC:

Heteronuclear single quantum coherence

i.d:

Internal diameter

LC:

Liquid chromatography

MPLC:

Medium pressure liquid chromatography

MS:

Mass spectrometry or mass spectrometer

NMR:

Nuclear magnetic resonance spectroscopy or nuclear magnetic resonance spectrometer

NOESY:

Nuclear Overhauser effect spectroscopy

RAD:

Radiometric detector

ROESY:

Rotating frame Overhauser effect spectroscopy

SGLT2:

Sodium-glucose cotransporter 2

TOCSY:

Total correlation spectroscopy

UV:

Ultraviolet

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ACKNOWLEDGMENTS AND DISCLOSURES

The author thanks Mr. Aiji Miyashita, Mr. Kinya Soda, Ms Masami Watanabe, Dr. Fumihiko Ushigome, Mr. Katsuhiro Suzuki, Dr. Yasuhisa Nagasaka, Mr. Kinya Souda, Dr. Mitsuhiro Sekiguchi, Dr. Kazuyoshi Nozaki, Dr. Akio Kawamura, Dr. Takafumi Iwatsubo, Dr. Takashi Usui and Dr. Hidetaka Kamimura (Astellas Pharma Inc.) and Mr. Yoshihiko Haino (Kotobuki Pharmaceutical) for their useful advice.

Naoyuki Nakada is an employee Astellas Pharma Inc. No funding has been received for the conduct of this study.

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Authors and Affiliations

  1. Analysis & Pharmacokinetics Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Miyukigaoka 21, Tsukuba-shi, Ibaraki, 305-8585, Japan

    Naoyuki Nakada

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  1. Naoyuki Nakada
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Correspondence to Naoyuki Nakada.

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Nakada, N. Evaluation of the Utility of Chimeric Mice with Humanized Livers for the Characterization and Profiling of the Metabolites of a Selective Inhibitor (YM543) of the Sodium-Glucose Cotransporter 2. Pharm Res 34, 874–886 (2017). https://doi.org/10.1007/s11095-017-2116-4

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  • DOI: https://doi.org/10.1007/s11095-017-2116-4

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