Background: Tenofovir disoproxil fumarate, a prodrug of the nucleotide reverse transcriptase inhibitor, tenofovir (9-[9(R)-2-(phosphonomethoxy)propyl]adenine; PMPA), was recently approved for use in the combination therapy of human immunodeficiency virus (HIV)-1 infection. This study was undertaken to understand PMPA distribution to the virus sanctuary sites located in the brain, CSF and choroid plexuses and to clarify its possible role in reducing the neurological problems associated with HIV infection.
Methods: The methods used included an established bilateral carotid artery perfusion of [3H]PMPA and a vascular marker, D-[14C]mannitol, in anaesthetised guinea-pigs followed by scintillation counting, HPLC and capillary depletion analyses. Movement of [3H]PMPA into the brain, cisternal CSF and lateral ventricle choroid plexus was also examined in the absence and presence of additional anti-HIV drugs and a transport inhibitor. Control and test groups were compared by ANOVA or Student's t-test, as appropriate.
Results: The distribution of [3H]PMPA in the cerebrum, cerebellum, pituitary gland and cerebral capillary endothelial cells was not significantly different to that measured for D-[14C]mannitol. However, [3H]PMPA accumulation was significantly higher than that of D-[14C]mannitol in the choroid plexus and CSF. Further experiments revealed no cross-competition for transport of [3H]PMPA by probenecid, a non-specific inhibitor of organic anion transport, or the nucleoside reverse transcriptase inhibitors into any of the CNS regions studied. The octanol-saline partition coefficient measurement for [3H]PMPA was 0.0134 +/- 0.00003, which is higher that the 0.002 +/- 0.0004 measured for D-[14C]mannitol in an earlier study.
Conclusion: There is negligible transport of [3H]PMPA across the blood-brain barrier, but it can cross the blood-CSF barrier. This is a reflection of the differing physiological and functional characteristics of the blood-CNS interfaces. Self- and cross-inhibition studies did not suggest the involvement of a transport system in the CNS distribution of this drug. However, the ability of PMPA to accumulate in the choroid plexus tissue, but not the cerebral capillary endothelial cells, and the hydrophilic nature of PMPA, does point to the possibility of a transporter at the level of the choroid plexus. PMPA that has crossed the choroid plexus and is in the CSF could treat HIV-infected perivascular and meningeal macrophages, but it is unlikely to reach the infected microglia of deep brain sites.