THE PHARMACOKINETICS AND BLOOD-BRAIN-BARRIER PERMEATION OF THE CHELATORS 1,2-DIMETHYL-HYDROXYPYRIDIN-4-ONE, 1,2-DIETHYL-HYDROXYPYRIDIN-4-ONE, AND 1-[ETHAN-1'OL]-2-METHYL-3-HYDROXYPYRIDIN-4-ONE IN THE RAT

The 3-hydroxypyridin-4-ones (HPs) are iron and aluminium chelators. Th eir ability to enter the brain had not previously been directly determ ined. To determine whether they cross the blood-brain barrier (BBB), t hree HPs possessing a wide range of lipophilicity were examined: 1-[et han-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-diethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determ ined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis prob es in the blood, frontal cortex, and lateral ventricle to determine th e rate and extent of HP BBB permeability, All three HPs were detectabl e in brain dialysate samples collected 0-7 min after HP injection, dem onstrating rapid entry into the brain, The extent of unbound distribut ion (an indicator of the mechanism of BBB permeation) was 0.9 and 1.2 for the frontal cortex and lateral ventricle for CP20, and was 1.1 and 1.6 for CP94, suggesting diffusion across the BBB, The extent of unbo und distribution of CP40 was 0.2 for both the frontal cortex and later al ventricle, suggesting the presence of a transporter moving it out o f brain extracellular fluid. Introduction of cyanide into the brain di d not affect the brain to blood CP40 ratio, suggesting that the transp orter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic b identate HP chelators, such as CP20, to enter the brain may enable the ir use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.