Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 infection.
Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases including human immunodeficiency virus type-1 (HIV-1) encephalitis (HIVE). One mechanism that may contribute to this phenomenon is the expression of ATP-binding cassette (ABC) drug efflux transporters [i.e., P-glycoprotein (P-gp), Multidrug Resistance-Associated Proteins (MRP/Mrp), Breast Cancer Resistance Protein (BCRP; also known as ABCG2)] at the primary brain barrier sites (i.e., blood-brain barrier, blood-cerebrospinal fluid barrier). In addition, it has been recently proposed that glial cells may also contribute to the low accumulation and altered distribution of therapeutic compounds in the CNS by functioning as a "secondary barrier." In fact, a few studies have shown that ABC transporters are both expressed and functional in glial cells. Furthermore, commonly prescribed antiretroviral compounds (ARVs), particularly HIV-1 protease inhibitors, are substrates for many of these same transport proteins suggesting that ABC transporters in glial cells may contribute to the overall export of these drugs from the brain. HIV-1 infection is a chronic condition characterized by long-term exposure of brain cellular compartments to HIV-1 virions and soluble viral proteins. In addition, treatment of HIV-1 infection involves long-term administration of a multiplicity of ARVs (i.e., HAART regimens). Indeed, pathological factors associated with HIV-1 infection and/or pharmacological factors related to treatment may alter the expression of ABC transporters and lead to changes in CNS ARV uptake and/or distribution. This review summarizes recent knowledge in this area and emphasizes the role that glial ABC transporters may play in regulating ARV transport.
Ronaldson
Patrick T
PT
Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Persidsky
Yuri
Y
Bendayan
Reina
R
D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000821:virology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D009457:Neuroglia / Q000378:metabolism* / Q000821:virology
D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents