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.
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.
Authors: P Krogstad; A Wiznia; K Luzuriaga; W Dankner; K Nielsen; M Gersten; B Kerr; A Hendricks; B Boczany; M Rosenberg; D Jung; S A Spector; Y Bryson Journal: Clin Infect Dis Date: 1999-05 Impact factor: 9.079
Authors: D J Kempf; K C Marsh; J F Denissen; E McDonald; S Vasavanonda; C A Flentge; B E Green; L Fino; C H Park; X P Kong Journal: Proc Natl Acad Sci U S A Date: 1995-03-28 Impact factor: 11.205
Authors: David Croteau; Steven S Rossi; Brookie M Best; Edmund Capparelli; Ronald J Ellis; David B Clifford; Ann C Collier; Benjamin B Gelman; Christina M Marra; Justin McArthur; J Allen McCutchan; Susan Morgello; David M Simpson; Igor Grant; Scott Letendre Journal: J Antimicrob Chemother Date: 2012-11-09 Impact factor: 5.790
Authors: David Croteau; Scott Letendre; Brookie M Best; Steven S Rossi; Ronald J Ellis; David B Clifford; Ann C Collier; Benjamin B Gelman; Christina M Marra; Justin McArthur; J Allen McCutchan; Susan Morgello; David M Simpson; Lauren Way; Edmund Capparelli; Igor Grant Journal: Antimicrob Agents Chemother Date: 2012-01-30 Impact factor: 5.191
Authors: Sreeja Sudhakaran; Craig R Rayner; Jian Li; David C M Kong; Neil M Gude; Roger L Nation Journal: Br J Clin Pharmacol Date: 2007-12-17 Impact factor: 4.335