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.
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 (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.
authors.affiliation: Department of Clinical Chemistry and Informatics, Graduate School of Pharmaceutical Sciences, Kumamoto University.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Yusei
authors.initials: Y
authors.lastname: Yamada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ishitsuka
authors.forename: Muneaki
authors.initials: M
authors.lastname: Matsuo
authors.forename: Koki
authors.initials: K
authors.lastname: Shiraishi
authors.forename: Koki
authors.initials: K
authors.lastname: Wada
authors.forename: Yushiro
authors.initials: Y
authors.lastname: Uchio
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kondo
authors.forename: Toru
authors.initials: T
authors.lastname: Takeo
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.forename: Taishi
authors.initials: T
authors.lastname: Higashi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Motoyama
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Arima
authors.forename: Sakiko
authors.initials: S
authors.lastname: Mochinaga
authors.forename: Katsumi
authors.initials: K
authors.lastname: Higaki
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohno
authors.forename: Tetsumi
authors.initials: T
authors.lastname: Irie
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000150:complications / Q000188:drug therapy*; D011506:Proteins / Q000235:genetics; D012995:Solubility; D047392:beta-Cyclodextrins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D002784:Cholesterol