RT Journal Article
SR Electronic
T1 Nevirapine Uptake into the Central Nervous System of the Guinea Pig: An in Situ Brain Perfusion Study
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 746
OP 751
DO 10.1124/jpet.105.098459
VO 317
IS 2
A1 J. E. Gibbs
A1 Z. Gaffen
A1 S. A. Thomas
YR 2006
UL http://jpet.aspetjournals.org/content/317/2/746.abstract
AB The presence of human immunodeficiency virus (HIV) in the central nervous system (CNS) is associated with the development of HIV-1-associated dementia (HAD), a major cause of HIV-related mortality. To eradicate HIV in the CNS, anti-HIV drugs need to reach the brain and cerebrospinal fluid (CSF) in therapeutic concentrations. This involves passage through the blood-brain and blood-CSF barriers. Using a well established guinea pig in situ brain perfusion model, this study investigated whether nevirapine [6H-dipyrido(3,2-b:2′,3′-e)(1,4)diazepin-6-one,11-cyclopropyl-5,11-dihydro-4-methyl], a non-nucleoside reverse transcriptase inhibitor (NNRTI), could effectively accumulate in the CNS. [3H]Nevirapine was coperfused with [14C]mannitol (a vascular/paracellular permeability marker) through the carotid arteries for up to 30 min, and accumulation in the brain, CSF, and choroid plexus was measured. [3H]Nevirapine uptake into the cerebrum was greater than uptake of [14C]mannitol, indicating significant passage across the blood-brain barrier and accumulation into the brain (this was further confirmed with capillary depletion and high-performance liquid chromatography analyses). Likewise, [3H]nevirapine showed a great ability to cross the blood-CSF barrier and accumulate in the CSF, compared with [14C]mannitol. The CNS accumulation of [3H]nevirapine was unaffected by 100 μM nevirapine, suggesting that passage across the blood-brain barrier can occur by diffusion. Furthermore, coperfusion with 100 μM efavirenz [2H-3,1-benzoxazin-2-one, 6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-, (4S)-; another NNRTI] did not significantly alter CNS accumulation of [3H]nevirapine, indicating that the efficacy of nevirapine in the CNS would not be altered by the addition of this drug to a combination therapy. Together, these data indicate that this anti-HIV drug should be beneficial in the eradication of HIV within the CNS and the subsequent treatment of HAD. The American Society for Pharmacology and Experimental Therapeutics