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NEUROPHARMACOLOGY

Nevirapine Uptake into the Central Nervous System of the Guinea Pig: An in Situ Brain Perfusion Study

Pharmaceutical Sciences Research Division, King's College London, London, United Kingdom

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.

Address correspondence to: Dr. Sarah Ann Thomas, King's College London, Pharmaceutical Sciences Research Division, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK. E-mail: sarah.thomas{at}kcl.ac.uk

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