Quantitative Assessment of HIV-1 Protease Inhibitor Interactions with Drug Efflux Transporters in the Blood–Brain Barrier
- First Online:
- 197 Downloads
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.
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.
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.
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.
Key WordsBCECF blood–brain barrier HIV-1 protease inhibitors
bovine brain microvessel endothelial cells
brain cancer resistance protein
central nervous system
highly active retroviral therapy
human immunodeficiency virus
multidrug resistance–associated protein
organic anion transporter
organic anion transporting peptide