The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses

被引：36

作者：

Anthonypillai C. ^{[1
]}

Gibbs J.E. ^{[1
,2
]}

Thomas S.A. ^{[1
]}

机构：

[1] King's College London, Wolfson Centre for Age-Related Diseases, London SE1 1UL, Guy's Campus, Hodgkin Building

[2] Department of Clinical Neurosciences, Epilepsy Group, St Georges University of London, London SW17 0RE, Cranmer Terrace

来源：

Cerebrospinal Fluid Research | / 3卷 / 1期

关键词：

Human Immunodeficiency Virus; Mannitol; Human Immunodeficiency Virus Infection; Tenofovir; Choroid Plexus;

D O I：

10.1186/1743-8454-3-1

中图分类号：

学科分类号：

摘要：

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)-I 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. © 2006 Anthonypillai et al; licensee BioMed Central Ltd.

引用

共 58 条

[11]

Schrager L.K., D'Souza M.P., Cellular and anatomical reservoirs of HIV-1 in patients receiving potent antiretroviral combination therapy, JAMA, 280, pp. 67-71, (1998)

[12]

Wong J.K., Hezareh M., Gunthard H.F., Havlir D.V., Ignacio C.C., Spina C.A., Richman D.D., Recovery of replication-competent HIV despite prolonged suppression of plasma viremia, Science, 278, pp. 1291-1295, (1997)

[13]

Siliciano J.D., Siliciano R.F., Latency and viral persistence in HIV-1 infection, J Clin Invest, 106, pp. 823-825, (2000)

[14]

Chun T.W., Fauci A.S., Latent reservoirs of HIV: Obstacles to the eradication of virus, Proc Natl Acad Sci U S A, 96, pp. 10958-10961, (1999)

[15]

Aquaro S., Bagnarelli P., Guenci T., De Luca A., Clementi M., Balestra E., Calio R., Perno C.F., Long-term survival and virus production in human primary macrophages infected by human immunodeficiency virus, J Med Virol, 68, pp. 479-488, (2002)

[16]

Crowe S.M., Mills J., Kirihara J., Boothman J., Marshall J.A., McGrath M.S., Full-length recombinant CD4 and recombinant gp 120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells, AIDS Res Hum Retroviruses, 6, pp. 1031-1037, (1990)

[17]

Smith B.A., Gartner S., Liu Y., Perelson A.S., Stilianakis N.I., Keele B.F., Kerkering T.M., Ferreira-Gonzalez A., Szakal A.K., Tew J.G., Burton G.F., Persistence of infectious HIV on follicular dendritic cells, J Immunol, 166, pp. 690-696, (2001)

[18]

Gunthard H.F., Havlir D.V., Fiscus S., Zhang Z.Q., Eron J., Mellors J., Gulick R., Frost S.D., Brown A.J., Schleif W., Valentine F., Jonas L., Meibohm A., Ignacio C.C., Isaacs R., Gamagami R., Emini E., Haase A., Richman D.D., Wong J.K., Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years, J Infect Dis, 183, pp. 1318-1327, (2001)

[19]

McArthur J.C., McClernon D.R., Cronin M.F., Nance-Sproson T.E., Saah A.J., St Clair M., Lanier E.R., Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain, Ann Neurol, 42, pp. 689-698, (1997)

[20]

Arendt G., von Giesen H.J., Hefter H., Theisen A., Therapeutic effects of nucleoside analogues on psychomotor slowing in HIV infection, AIDS, 15, pp. 493-500, (2001)

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