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Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease

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Abstract

Purpose

Menkes disease is a rare hereditary disease in which systemic deficiency of copper due to mutation of the ATP7A gene causes severe neurodegenerative disorders. The present parenteral drugs have limited efficacy, so there is a need for an efficacious drug that can be administered orally. This study focused on glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II (CuGTSM), which has shown efficacy in macular mice, a murine model of Menkes disease, and examined its pharmacokinetics. In addition, nanosized CuGTSM (nCuGTSM) was prepared, and the effects of nanosizing on CuGTSM pharmacokinetics were investigated.

Methods

CuGTSM or nCuGTSM (10 mg/kg) was administered orally to male macular mice or C3H/HeNCrl mice (control), and plasma was obtained by serial blood sampling. Plasma concentrations of CuGTSM and GTSM were measured by LC-MS/MS and pharmacokinetic parameters were calculated.

Results

When CuGTSM was administered orally, CuGTSM and GTSM were both detected in the plasma of both mouse strains. When nCuGTSM was administered, the Cmax was markedly higher, and the mean residence time was longer than when CuGTSM was administered for both CuGTSM and GTSM in both mouse strains. With macular mice, the AUC ratio (GTSM/CuGTSM) was markedly higher and the plasma CuGTSM concentration was lower than with C3H/HeNCrl mice when either CuGTSM or nCuGTSM was administered.

Conclusion

Absorption of orally administered CuGTSM was confirmed in macular mice, and the nano-formulation improved the absorption and retention of CuGTSM in the body. However, the plasma concentration of CuGTSM was lower in macular mice than in control mice, suggesting easier dissociation of CuGTSM.

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Abbreviations

AUC:

Area under the concentration-time curve

AUMC:

Area under the first moment curve

BBB:

Blood-brain barrier

Cmax :

Maximum plasma concentration

Cu:

Copper

CuATSM:

Diacetyl-bis(N(4)-methylthiosemicarbazonato)-copper(II)

CuBTSCs:

Copper(II) bis(thiosemicarbazones)

CuGTSM:

Glyoxal-bis (N(4)-methylthiosemicarbazonato)-copper(II)

Cu(OAc)2 :

Copper(II) acetate monohydrate

CuPTSM:

Pyruvaldehyde bis(N(4)-methylthiosemicarbazonato)-copper(II)

DEDTC:

Diethyldithiocarbamate

DMDTC:

Dimethyldithiocarbamate

IS:

Internal standard

MRT:

Mean residence time

MW:

Molecular weight

nCuGTSM:

Nanosized CuGTSM

QOL:

Quality of life

SDS:

Sodium dodecyl sulfate

SSV:

Standard suspension vehicle

T1/2 :

Elimination half-life

Tmax :

Time to maximum plasma concentration

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Acknowledgments and Disclosures

We thank Dr. Yoshimasa Sakamoto, Dr. Yukari Takase and Ms. Yuko Hino for breeding C3H/HeNCrl mice and macular mice. The authors declare that they have no conflict of interest.

Funding

This work was supported by JSPS KAKENHI Grant Number JP18K06762.

Author information

Author notes

  1. Yoshiaki Yamagishi and Toshiyuki Kudo contributed equally to this work.

Authors and Affiliations

  1. Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan

    Yoshiaki Yamagishi, Toshiyuki Kudo, Masafumi Oyumi, Yusuke Sakamoto, Shohei Kobayashi, Takeaki Kawakami, Hitomi Goda & Kiyomi Ito

  2. Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan

    Kazuki Takahashi, Taiki Akashi & Toshiro Fukami

  3. Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan

    Yasuhiro Sato & Masakazu Mimaki

  4. Health and Dietetics, Teikyo Heisei University, Graduate School of Health Sciences, Tokyo, Japan

    Hiroko Kodama

  5. Department of Pediatrics, Tohoku University School of Medicine, Miyagi, Japan

    Mitsutoshi Munakata

  6. Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan

    Kosho Makino & Hideyo Takahashi

Authors
  1. Yoshiaki Yamagishi
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Contributions

Yoshiaki Yamagishi and Toshiyuki Kudo contributed equally to this work. Yoshiaki Yamagishi, Toshiyuki Kudo, Toshiro Fukami and Kiyomi Ito contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yoshiaki Yamagishi, Toshiyuki Kudo, Masafumi Oyumi, Yusuke Sakamoto, Kazuki Takahashi, Taiki Akashi, Shohei Kobayashi, Takeaki Kawakami, Hitomi Goda, Hiroko Kodama, Yasuhiro Sato, Mitsutoshi Munakata, Kosho Makino and Hideyo Takahashi. The first draft of the manuscript was written by Yoshiaki Yamagishi, Toshiyuki Kudo, Taiki Akashi, Hideyo Takahashi, Toshiro Fukami and Kiyomi Ito. All authors read and approved the final manuscript.

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Correspondence to Kiyomi Ito.

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Yamagishi, Y., Kudo, T., Oyumi, M. et al. Pharmacokinetics of CuGTSM, a Novel Drug Candidate, in a Mouse Model of Menkes Disease. Pharm Res 38, 1335–1344 (2021). https://doi.org/10.1007/s11095-021-03090-0

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