Received for publication November 10, 2005.
Revised January 18, 2006.
Accepted for publication January 18, 2006.

Nevirapine uptake into the CNS of the guinea-pig: an in situ brain perfusion study

Abstract

The presence of human immunodeficiency virus (HIV) in the 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 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, a non-nucleoside reverse transcriptase inhibitor (NNRTI), could effectively accumulate in the CNS. [³H]nevirapine was co-perfused 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 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 HPLC analyses). Similarly [³H]nevirapine showed a great ability to cross the blood-CSF barrier and accumulate in the CSF, when compared to [¹⁴C]mannitol. The CNS accumulation of [³H]nevirapine was unaffected by 100µM nevirapine suggesting that passage across the blood-brain barrier can occur by diffusion. Furthermore co-perfusion with 100µM efavirenz (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 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.

Key words: HIV, blood-brain barrier, brain, cerebrospinal fluid, choroid plexuses, transport

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