PIOGLITAZONE CSF PENETRATION TO TREAT PARKINSON'S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: To assess penetration of pioglitazone into the cerebral spinal fluid (CSF). This project is completed: Pioglitazone, a thiazoledionedione currently FDA approved as an antidiabetic treatment, has been proposed as a neuroprotective therapy for neurological disorders. We previously demonstrated in nonhuman primates that daily oral pioglitazone dosing protects against the functional and anatomical effects of the parkinsogenic toxin MPTP. In this study we continued our clinical translation analysis of this compound by analyzing the ability of different doses of pioglitazone to penetrate the CSF. Five adult female rhesus monkeys (5-6 kg) received once daily oral administration of placebo, 2.5 mg/kg, 5.0 mg/kg mg or 7.5 mg /kg of pioglitazone for 7 days. There was a lapse of 1 week between a change in dose and plasma and CSF sampling to allow for steady state. Plasma and CSF samples were obtained at each baseline and 5 hours after the last dose of pioglitazone. Levels of pioglitazone were evaluated by HPLC methods. In plasma, comparison between pioglitazone levels showed, as expected, that administration of 5 mg/kg induced higher levels than 2.5 mg/kg. Yet, in four of the five monkeys 7.5 mg/kg dosing did not result in consistently higher increases of pioglitazone plasma levels compared to 5 mg/kg. These data suggest increased drug elimination with 7.5 mg/kg. CSF levels of pioglitazone compared to plasma showed more individual variability. A dose of 2.5 mg/kg induced non-detectable levels in two of the five animals. Both, 5 and 7.5 mg/kg had consistent measurable levels in CSF. Four of the five monkeys had higher CSF levels of pioglitazone after receiving 5 mg/kg compared to 7.5 mg/kg. The results confirmed the ability of pioglitazone to penetrate CSF and suggest that in rhesus monkeys 5 mg/kg was an efficient dose to consistently induce detectable higher levels of pioglitazone in plasma and CSF. This research used CPI and Assay Services. Funding has ended; a publication has been submitted.