Brain and CSF entry of the novel non-nucleoside reverse transcriptase inhibitor, GW420867X.
(S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) inhibits HIV-1 reverse transcriptase and could be used for the treatment of HIV infection. This study quantified the movement of [14C]GW420867X into the CNS by means of a guinea-pig brain perfusion technique. Results indicated that [14C]GW420867X can enter the brain (Kin: 38.4+/-7.7 microl min(-1) g(-1)) and cerebrospinal fluid (CSF; Kin: 1.2+/-0.1 microl min(-1) g(-1)). Self-inhibition studies also suggested the presence of a saturable transport system for [14C]GW420867X at the blood-brain barrier (BBB). Thus [14C]GW420867X can enter the brain via the BBB and, compared with the blood-CSF barrier, this route is the predominant pathway for the brain entry of this drug. This would suggest that GW420867X is a promising drug for the treatment of HIV infection within the brain.
Thomas
S
S
Neural Damage and Repair, Centre for Neuroscience, Division of Physiology, Guy's, King's and St. Thomas' School of Biomedical Science, King's College London, UK.
Cass
L
L
Prince
W
W
Segal
M
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D008353:Mannitol / Q000493:pharmacokinetics; D011810:Quinoxalines / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D012995:Solubility
C402066:GW420867X; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D008353:Mannitol