Abstract

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.