HIV Research Today is a free monthly online journal that collates and summarizes the latest research about HIV, including details on human immunodeficiency virus, testing, treatment, prevention, vaccines, aids.

Quantitative assessment of HIV-1 protease inhibitor interactions with drug efflux transporters in the blood-brain barrier.

Bachmeier CJ, Spitzenberger TJ, Elmquist WF, Miller DW

Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, Nebraska, USA.

PURPOSE: To quantitatively characterize the drug efflux interactions of various HIV-1 protease inhibitors in an in vitro model of the blood-brain barrier (BBB) and to compare that with HIV-1 protease inhibitor stimulated P-glycoprotein (P-gp)-ATPase activity. METHODS: Cellular accumulation of the P-gp sensitive probe, rhodamine 123 (R123), and the mixed P-gp/multidrug resistance-associated protein (MRP) probe, 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF), were evaluated in primary cultured bovine brain microvessel endothelial cells (BBMEC) in the presence of various concentrations of HIV-1 protease inhibitors. The potency (IC50) and efficacy (Imax) of the drugs in the cell accumulation assays for P-gp and/or MRP was determined and compared to activity in a P-gp ATPase assay. RESULTS: For R123 (P-gp probe), the rank order potency for inhibiting R123 accumulation in the BBMEC was saquinavir=nelfinavir>ritonavir=amprenavir>indinavir. This correlated well with the rank order affinity in the P-gp ATPase assay. The rank order potency for MRP-related drug efflux transporters, was nelfinavir>ritonavir>saquinavir>amprenavir>indinavir. CONCLUSIONS: HIV-1 protease inhibitors potently interact with both P-gp and MRP-related transporters in BBMEC. Characterization of the interactions between the HIV-1 protease inhibitors and drug efflux transporters in brain microvessel endothelial cells will provide insight into potential drug-drug interactions and permeability issues in the BBB.

Published 3 August 2005 in Pharm Res, 22(8): 1259-68.
Full-text of this article is available online (may require subscription).

© 2004-2008 HIV Research Today. All Rights Reserved.