pgp - publications

Predict more pgp - ligand interactions now!

Induction of P-glycoprotein by Antiretroviral Drugs in Human Brain Microvessel Endothelial Cells.

Antimicrob Agents Chemother. 2013 Jul 8;

Authors: Chan GN, Patel R, Cummins CL, Bendayan R


The membrane-associated drug transporter, P-glycoprotein (P-gp), plays an essential role in drug efflux from the brain. Induction of this protein at the blood-brain barrier (BBB) could further affect drug permeability into the brain. At present, P-gp induction at the BBB mediated by antiretroviral drugs has not been fully investigated. Since P-gp expression is regulated by ligand-activated nuclear receptors i.e., human Pregnane X Receptor (hPXR) and human Constitutive Androstane Receptor (hCAR), these receptors could represent potential pathways involved in P-gp induction by antiretroviral drugs. The aims of this study were: i) to determine whether antiretroviral drugs currently used in HIV pharmacotherapy are ligands for hPXR or hCAR and ii) to examine P-gp function and expression in human brain microvessel endothelial cells treated with antiretroviral drugs identified as ligands of hPXR and/or hCAR. Luciferase reporter gene assays were performed to examine the activation of hPXR and hCAR by antiretroviral drugs. The hCMEC/D3 cell line, known to display several morphological and biochemical properties of the BBB in humans, was utilized to examine P-gp induction following 72 h exposure to these agents. Amprenavir, atazanavir, darunavir, efavirenz, ritonavir and lopinavir were found to activate hPXR, whereas, abacavir, efavirenz and nevirapine were found to activate hCAR. P-gp expression and function were significantly induced in hCMEC/D3 cells treated with these drugs at clinical plasma concentrations. Together, our data suggest that P-gp induction could occur at the BBB during chronic treatment with antiretroviral drugs identified to be ligands of hPXR and/or hCAR.

PMID: 23836171 [PubMed - as supplied by publisher]