Efficacy of 2-Hydroxypropyl-β-cyclodextrin in Niemann–Pick Disease Type C Model Mice and Its Pharmacokinetic Analysis in a Patient with the Disease

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Author(s)

    • Tanaka Yuta Tanaka Yuta
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Motoyama Keiichi
    • Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Arima Hidetoshi
    • Department of Physical Pharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Higaki Katsumi
    • Division of Functional Genomics, Research Center for Bioscience and Technology, Faculty of Medicine, Tottori University
    • Irie Tetsumi
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Yamada Yusei
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Ishitsuka Yoichi
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Shiraishi Koki
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Wada Koki
    • Research Institute, Nihon Shokuhin Kako Co., Ltd.
    • Uchio Yushiro
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Kondo Yuki
    • Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University
    • Takeo Toru
    • Division of Reproductive Engineering, Center for Animal Resources and Development (CARD), Kumamoto University

Abstract

Niemann–Pick type C disease (NPC), an autosomal recessive lysosomal storage disorder, is an inherited disease characterized by the accumulation of intracellular unesterified cholesterol. A solubilizing agent of lipophilic compounds, 2-hydroxypropyl-β-cyclodextrin (HPBCD), is an attractive drug candidate against NPC disease. However, establishment of the optimum dosage of HPBCD remains to be determined. In this study, we evaluated the effective dosage of HPBCD in NPC model (<i>Npc1</i><sup>−/−</sup>) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000–4000 mg/kg HPBCD improved the lifespan of <i>Npc1</i><sup>−/−</sup> mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in <i>Npc1</i><sup>−/−</sup> mice. Serum HPBCD concentrations, when treated at the effective dosages (1000–4000 mg/kg), were approximately 1200–2500 µg/mL at 0.5 h after subcutaneous injection, and blood HPBCD concentrations were immediately eliminated in <i>Npc1</i><sup>−/−</sup> mice. Furthermore, we examined serum HPBCD concentrations when treated at 40000 mg (approximately 2500 mg/kg) in a patient with NPC. We observed that the effective concentration in the <i>in vivo</i> study using <i>Npc1</i><sup>−/−</sup> mice was similar to that in the patient. In the patient, systemic clearance and the volume of distribution of HPBCD were in accordance with the glomerular filtration rate and extracellular fluid volume, respectively. These results could provide useful information for developing the optimal dosage regimen for HPBCD therapy when administered intravenously to NPC patients.

Journal

  • Biological and Pharmaceutical Bulletin

    Biological and Pharmaceutical Bulletin 38(6), 844-851, 2015

    The Pharmaceutical Society of Japan

Codes

  • NII Article ID (NAID)
    130005072664
  • NII NACSIS-CAT ID (NCID)
    AA10885497
  • Text Lang
    ENG
  • ISSN
    0918-6158
  • NDL Article ID
    026408186
  • NDL Call No.
    Z53-V41
  • Data Source
    NDL  J-STAGE 
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