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The neuroprotective agent NXY-059 is detected in rat brain following exposure at a clinically attainable plasma concentration
NXY-059 is a neuroprotectant with free radical trapping properties and efficacy in animal models of transient and permanent focal ischaemia (Green et al., 2003) and is in clinical development for the treatment of acute ischaemic stroke. In vitro (Dehouck et al., 2002) and in vivo (Kuroda et al., 1999) blood-brain barrier (BBB) permeability studies demonstrated low brain uptake of the drug. We have now examined the concentration of NXY-059 in the brain following its infusion to rats with a permanent middle cerebral artery occlusion (pMCAO) at a dose that produced a clinically attainable plasma level of around 200 µmol l-1 (Lees et al., 2003). S-D rats (250-300 g) were subjected to pMCAO with an intraluminal thread (Sydserff et al., 2002). Beginning 15 min post-occlusion NXY-059 (125 mg kg-1) was injected as an iv bolus, followed by infusion (125 mg kg-1 h-1) for a further 4h 45min. A second group received a sham operation and the same dosing regime. Just prior to the end of infusion a 0.5 ml blood sample was withdrawn for subsequent analysis of NXY-059. At 5h, following a wash-out of the drug from blood vessels, animals were killed, the right and left cortex dissected for subsequent analysis of the cerebral NXY-059 concentration. Plasma and cortex NXY-059 concentration was measured by HPLC and UV detection. The plasma total drug concentration at 5h was similar in the 2 groups (Table 1). The concentration of NXY-059 was also similar in the right (ischaemic) and left (ipsilateral) cortex of the pMCAO rats and the 2 sides of the sham operated rats (Table 1). NXY-059 is approximately 70% protein bound in rat plasma, thus the ‘free’ NXY-059 concentration achieved is approximately 190 µmol l-1. The drug in the brain can be assumed to be primarily in extracellular fluid, since it has poor cellular penetration (Dehouck et al., 2002). Extracellular fluid is approximately 20% of brain mass (Nicholson & Syková, 1998), so the 6-7 nmol g-1 [6 µM] measured in cortex suggests an extracellular NXY-059 concentration of over 30 µM. We conclude that a clinically attainable plasma concentration of NXY-059 produces a pharmacologically relevant concentration of the drug in the brain, despite low BBB permeability. Table 1. Total NXY-059 concentration in plasma ( m mol l-1) and cortex (nmol g-1) at 5 h in sham and pMCAO treated rats.
Results expressed as mean ± s.e. mean (n). Dehouck M-P et al. (2002) Brain Res.955, 229-235. |