Search

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 [14C]‐HP‐β‐CD (approximately 200 μCi/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‐β‐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‐β‐CD‐derived radioactivity penetrated into the deeper parts of the central nervous system with the highest concentration at 4 hours (403 μg Eq/g or 0.28 mM) and remained high (49.7 μg 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‐β‐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. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [14C]MEP or [14C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [14C]MEP or [14C]DEP (164 μg/kg). The absorption, metabolism, excretion and pharmacokinetics of [14C]MEP and [14C]DEP were nearly identical. [14C]DEP was rapidly and nearly completely metabolized to [14C]MEP following either intravenous or oral administration. [14C]MEP and[14C]DEP were rapidly absorbed, the elimination half-life was estimated to be 1 hour. Approximately 90%–96% of the dose was excreted in urine with 2%–3% of the dose in faeces. MEP accounted for the majority of the dose in plasma and urine; in addition, three minor metabolites (M1, M2 and M3) were detected. The minor metabolites were neither phthalic acid nor glucuronide/sulfate conjugates. The nearly identical metabolism and pharmacokinetics of MEP and DEP in juvenile dogs justifies the use of DEP toxicity data in the risk assessment of MEP exposure. [ABSTRACT FROM AUTHOR]

2-Hydroxypropyl-β-cyclodextrin (HP-β-CD), a widely used excipient for drug formulation, has emerged as an investigational new drug for the treatment of Niemann-Pick type C1 (NPC1) disease, a neurodegenerative cholesterol storage disorder. Development of a sensitive quantitative LC-MS/MS assay to monitor the pharmacokinetics (PKs) of HP-β-CD required for clinical trials has been challenging owing to the dispersity of the HP-β-CD. To support a phase 1 clinical trial for ICV delivery of HP-β-CD in NPC1 patients, novel methods for quantification of HP-β-CD in human plasma and cerebrospinal fluid (CSF) using LC-MS/MS were developed and validated: a 2D-LC-in-source fragmentation-MS/MS (2D-LC-IF-MS/MS) assay and a reversed phase ultra performance LC-MS/MS (RP-UPLC-MS/MS) assay. In both assays, protein precipitation and "dilute and shoot" procedures were used to process plasma and CSF, respectively. The assays were fully validated and in close agreement, and allowed determination of PK parameters for HP-β-CD. The LC-MS/MS methods are ∼100-fold more sensitive than the current HPLC assay, and were successfully employed to analyze HP-β-CD in human plasma and CSF samples to support the phase 1 clinical trial of HP-β-CD in NPC1 patients., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

The pharmacokinetics, metabolism and excretion of monoethyl phthalate (MEP) and diethyl phthalate (DEP) were compared after intravenous or oral administration of [(14)C]MEP or [(14)C]DEP in juvenile beagle dogs. Four male juvenile beagle dogs were treated with a single oral or bolus intravenous dose of either [(14)C]MEP or [(14)C]DEP (164 μg/kg). The absorption, metabolism, excretion and pharmacokinetics of [(14)C]MEP and [(14)C]DEP were nearly identical. [(14)C]DEP was rapidly and nearly completely metabolized to [(14)C]MEP following either intravenous or oral administration. [(14)C]MEP and[(14)C]DEP were rapidly absorbed, the elimination half-life was estimated to be 1 hour. Approximately 90%-96% of the dose was excreted in urine with 2%-3% of the dose in faeces. MEP accounted for the majority of the dose in plasma and urine; in addition, three minor metabolites (M1, M2 and M3) were detected. The minor metabolites were neither phthalic acid nor glucuronide/sulfate conjugates. The nearly identical metabolism and pharmacokinetics of MEP and DEP in juvenile dogs justifies the use of DEP toxicity data in the risk assessment of MEP exposure.