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

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 candi...

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Published in:Biological & pharmaceutical bulletin 2015/06/01, Vol.38(6), pp.844-851
Main Authors: Tanaka, Yuta, Yamada, Yusei, Ishitsuka, Yoichi, Matsuo, Muneaki, Shiraishi, Koki, Wada, Koki, Uchio, Yushiro, Kondo, Yuki, Takeo, Toru, Nakagata, Naomi, Higashi, Taishi, Motoyama, Keiichi, Arima, Hidetoshi, Mochinaga, Sakiko, Higaki, Katsumi, Ohno, Kousaku, Irie, Tetsumi
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cited_by cdi_FETCH-LOGICAL-c416t-d4a188198ca002ca0db628f2557d29ae176660fb9dde4cf59acf0a6eb627ca903
cites cdi_FETCH-LOGICAL-c416t-d4a188198ca002ca0db628f2557d29ae176660fb9dde4cf59acf0a6eb627ca903
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creator Tanaka, Yuta
Yamada, Yusei
Ishitsuka, Yoichi
Matsuo, Muneaki
Shiraishi, Koki
Wada, Koki
Uchio, Yushiro
Kondo, Yuki
Takeo, Toru
Nakagata, Naomi
Higashi, Taishi
Motoyama, Keiichi
Arima, Hidetoshi
Mochinaga, Sakiko
Higaki, Katsumi
Ohno, Kousaku
Irie, Tetsumi
description 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 (Npc1−/−) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000–4000 mg/kg HPBCD improved the lifespan of Npc1−/− mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1−/− 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 Npc1−/− 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 in vivo study using Npc1−/− 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.
doi_str_mv 10.1248/bpb.b14-00726
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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 (Npc1−/−) mice, and determined serum HPBCD concentrations. Subcutaneous injection of 1000–4000 mg/kg HPBCD improved the lifespan of Npc1−/− mice. In addition, liver injury and cholesterol sequestration were significantly prevented by 4000 mg/kg HPBCD in Npc1−/− 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 Npc1−/− 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 in vivo study using Npc1−/− 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.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>26027824</pmid><doi>10.1248/bpb.b14-00726</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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source Free Full-Text Journals in Chemistry
subjects 2-Hydroxypropyl-beta-cyclodextrin
2-hydroxypropyl-β-cyclodextrin
Animals
beta-Cyclodextrins - administration & dosage
beta-Cyclodextrins - blood
beta-Cyclodextrins - pharmacokinetics
beta-Cyclodextrins - therapeutic use
Cholesterol - metabolism
Disease Models, Animal
Humans
Liver - drug effects
Liver - metabolism
Liver Diseases - etiology
Liver Diseases - metabolism
Liver Diseases - prevention & control
Male
Mice
Mice, Knockout
Niemann-Pick Disease, Type C - complications
Niemann-Pick Disease, Type C - drug therapy
Niemann–Pick type C
Npc1-deficient mouse
Proteins - genetics
Solubility
title 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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