The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat.
The 3-hydroxypyridin-4-ones (HPs) are iron and aluminum chelators. Their ability to enter the brain had not previously been directly determined. To determine whether they cross the blood-brain barrier (BBB), three HPs possessing a wide range of lipophilicity were examined: 1-[ethan-1'ol]-2-methyl-HP (CP40), 1,2-dimethyl-HP (CP20, L1, deferiprone), and 1,2-dimethyl-HP (CP94, EL1NEt). Their pharmacokinetics were determined in rats to establish dosing parameters for microdialysis studies of BBB permeation. Studies were then conducted with microdialysis probes in the blood, frontal cortex, and lateral ventricle to determine the rate and extent of HP BBB permeability. All three HPs were detectable in brain dialysate samples collected 0-7 min after HP injection, demonstrating rapid entry into the brain. The extent of unbound distribution (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 unbound distribution of CP40 was 0.2 for both the frontal cortex and lateral ventricle, suggesting the presence of a transporter moving it out of brain extracellular fluid. Introduction of cyanide into the brain did not affect the brain to blood CP40 ratio, suggesting that the transporter is not energy-dependent. Both CP94 and CP40 caused death due to respiratory failure, whereas CP20 did not. The ability of less toxic bidentate HP chelators, such as CP20, to enter the brain may enable their use in the treatment of metal-induced diseases and iron-facilitated oxidative injury involving the central nervous system.
Fredenburg
A M
AM
Graduate Center for Toxicology, University of Kentucky, Lexington 40536-0082, USA.
Sethi
R K
RK
Allen
D D
DD
Yokel
R A
RA
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D002552:Cerebral Ventricles / Q000378:metabolism; D002614:Chelating Agents / Q000493:pharmacokinetics*; D000077543:Deferiprone; D005625:Frontal Lobe / Q000378:metabolism; D007502:Iron Chelating Agents / Q000493:pharmacokinetics; D008297:Male; D017551:Microdialysis; D011728:Pyridones / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012966:Sodium Cyanide / Q000494:pharmacology
D002614:Chelating Agents; D007502:Iron Chelating Agents; D011728:Pyridones; C068543:1,2-diethyl-3-hydroxypyridin-4-one; D000077543:Deferiprone; C098211:1-(ethan-1-ol)-2-methyl-3-hydroxypyridin-4-one; D012966:Sodium Cyanide