Pharmaceutical Research

, Volume 22, Issue 8, pp 1259–1268

Quantitative Assessment of HIV-1 Protease Inhibitor Interactions with Drug Efflux Transporters in the Blood–Brain Barrier

  • Corbin J. Bachmeier
  • Timothy J. Spitzenberger
  • William F. Elmquist
  • Donald W. Miller
Research Paper

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.

Key Words

BCECF blood–brain barrier HIV-1 protease inhibitors 

Abbreviations

BBB

blood–brain barrier

BBMEC

bovine brain microvessel endothelial cells

BCA

bicinchoninic acid

BCECF

2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein

BCRP

brain cancer resistance protein

CNS

central nervous system

HAART

highly active retroviral therapy

HIV-1

human immunodeficiency virus

MRP

multidrug resistance–associated protein

OAT

organic anion transporter

OATP

organic anion transporting peptide

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Corbin J. Bachmeier
    • 1
  • Timothy J. Spitzenberger
    • 1
  • William F. Elmquist
    • 2
  • Donald W. Miller
    • 3
  1. 1.Department of Pharmaceutical SciencesUniversity of Nebraska Medical CenterOmahaUSA
  2. 2.Department of PharmaceuticsUniversity of MinnesotaMinneapolisUSA
  3. 3.Department of Pharmacology and TherapeuticsUniversity of ManitobaWinnipeg,Canada

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