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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Unbound plasma concentrations may predict neuroprotective brain concentrations: a brain microdialysis and pharmacokinetic study of enadoline in rats.

A rat brain microdialysis study of enadoline (CI-977), a k-opioid agonist, was conducted in nonanesthetized healthy rats to determine brain extracellular fluid (ECF) concentrations of CI-977 associated with neuroprotective subcutaneous (s.c.) doses. Three groups of 3 to 4 nonanesthetized yet restrained Sprague-Dawley rats with jugular cannulas and implanted brain (striatum) microdialysis probes received single s.c. doses of 0.3, 1.0, or 3.0 mg/kg CI-977. Blood and microdialysate samples were collected over a 12-hour period. Extent of rat plasma protein binding was 77.5%. Unbound plasma concentrations associated with neuroprotection were 10-50 ng eq/mL. At each dose, brain ECF concentration-time profiles (corrected for probe recovery) were nearly coincident with enadoline plasma unbound concentration-time profiles. Consequently, at each dose the ratio of AUCecf/AUCffplasma, (AUC = Area Under the concentration-time Curve; ffplasma = free fraction in plasma = unbound plasma) which represents the distribution of drug between plasma and brain, was determined to be unity within experimental error. These results suggest that unbound plasma concentrations may predict brain ECF concentrations of CI-977. Further, our findings allow us to postulate enadoline unbound brain ECF concentrations necessary for neuroprotection.[1]


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