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Pharmacokinetics and distribution of 2-hydroxypropyl-?-cyclodextrin following a single intrathecal dose to cats.


ABSTRACT: 2-Hydroxypropyl-?-cyclodextrin (HP-?-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1-/- mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [14 C]-HP-?-CD (approximately 200??Ci/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each of various time points up to 24?hours postdose for subsequent processing and quantitative whole-body autoradiographic analysis. HP-?-CD-derived radioactivity absorbed from the CBMC was widely distributed to cat tissues; most tissues were observed to have reached their highest concentration at 1?hour postdose. HP-?-CD-derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403??g?Eq/g or 0.28?mM) and remained high (49.7 ?g?Eq/g or 0.03?mM) at 24?hours. The relatively long half-life (11-30?hours) in cerebral ventricles and the subarachnoid space surrounding the brain and spinal cord might contribute to the efficacy of HP-?-CD in NPC1 cats. Other tissues with high concentrations of radioactivity were nasal turbinates, pituitary gland, and urinary bladder, while relatively low concentrations were observed in blood and bile.

SUBMITTER: Kao ML 

PROVIDER: S-EPMC7317750 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Pharmacokinetics and distribution of 2-hydroxypropyl-β-cyclodextrin following a single intrathecal dose to cats.

Kao Mark L ML   Stellar Susan S   Solon Eric E   Lordi Alfred A   Kasica Nicole N   Swain Gary G   Bagel Jessica H JH   Gurda Brittney L BL   Vite Charles H CH  

Journal of inherited metabolic disease 20191215 3


2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) is an experimental therapy for Niemann-Pick disease type C (NPC) that reduced neuronal cholesterol and ganglioside storage, reduced Purkinje cell death, and increased lifespan in npc1-/- mice and NPC1 cats. In this study, tissue distribution was investigated in normal cats that received a single 120-mg dose of [<sup>14</sup> C]-HP-β-CD (approximately 200 μCi/cat) via the cerebellomedullary cistern (CBMC) and lumbar cistern. One cat was euthanized at each  ...[more]

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