The Effects of Protease Inhibitors and Nonnucleoside Reverse Transcriptase Inhibitors on P-Glycoprotein Expression in Peripheral Blood Mononuclear Cells In Vitro

Chandler, Becky; Almond, Lisa; Ford, Jennifer Lynn; Owen, Andrew; Hoggard, Patrick G.; Khoo, Saye; Back, David

doi:10.1097/00126334-200308150-00001

Cited by 87 publications

(70 citation statements)

References 32 publications

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“…As well, results of MTT cell viability assays suggest that the concentrations of these agents used do not affect cell viability (data not shown). In the present study, P-gp induction in hCMEC/D3 cells mediated by treatment with ritonavir, atazanavir, lopinavir, darunavir, nevirapine, and efavirenz supports previous findings demonstrating that these drugs were able to induce P-gp expression in lymphocytes and intestinal and hepatic tissues (24,(40)(41)(42)(43)(44)(45)(46). Interestingly, efavirenz is the only drug that appears to serve as a ligand of both hPXR and hCAR.…”

Section: Discussionsupporting

confidence: 90%

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

Chan

Patel

Cummins

et al. 2013

Antimicrob Agents Chemother

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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 the ability of a drug to enter the brain. At present, P-gp induction mediated by antiretroviral drugs at the BBB 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, which is known to display several morphological and biochemical properties of the BBB in humans, was used to examine P-gp induction following 72 h of 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 concentrations in plasma. Together, our data suggest that P-gp induction could occur at the BBB during chronic treatment with antiretroviral drugs identified as ligands of hPXR and/or hCAR.

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Section: Discussionsupporting

confidence: 90%

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

Chan

Patel

Cummins

et al. 2013

Antimicrob Agents Chemother

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“…Indeed, efavirenz acts as an inducer of CYPs in vivo (4) and also induces P-gp in vitro (7,8,17). The findings of this study now indicate that efavirenz may also substantially induce the expression of a number of other important drug efflux transporters and also of the uptake transporters OATP3A1 /SLCO3A1 and OATP2B1/SLCO2B1.…”

Section: Discussionmentioning

confidence: 66%

“…Many antiviral agents including efavirenz are known to inhibit the proliferation of cultured cells if extracellular concentrations are high enough to induce toxic intracellular values (17). Because the equilibrium between extra-and intracellular concentrations is often regulated by efflux proteins, changes in efflux protein activity may alter the sensitivity of the cells to these compounds like it has been demonstrated for saquinavir, ritonavir, and lopinavir (12,18,19).…”

Section: Growth Inhibition Assaysmentioning

confidence: 99%

Induction of Multiple Drug Transporters by Efavirenz

et al. 2009

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Abstract. Efavirenz, an important component of human immunodeficiency virus 1 (HIV-1) therapy, causes substantial drug interactions as an inducer of cytochromes and the transporter ABCB1. So far its effect on the expression of other transporters is unknown. We therefore investigated the effect of long-term exposure of cells to efavirenz on expression of a large number of important drug transporters and on cell proliferation as a surrogate of intracellular availability. LS180 cells were used as a surrogate for the major site of drug interactions and Jurkat cells were used as a surrogate for the main target cells of HIV therapy. Cells were treated with efavirenz over 4 weeks and mRNA expression of drug transporters was repeatedly quantified. After 4 weeks, efavirenz significantly up-regulated the mRNA of ABCB1, ABCG2, ABCC2, ABCC3, ABCC5, and SLCO3A1 in LS180 cells and ABCG2, ABCC1, ABCC4, ABCC5, and SLCO2B1 in Jurkat cells. However these changes in transporter expression did not influence cell proliferation indicating that intracellular efavirenz concentrations were likely not altered. Efavirenz induces mRNA expression of several drug transporters critically modulating the kinetics of other drugs. While these expressional changes will most likely not influence the efficiency of efavirenz itself, they might change the effect of other co-administered drugs.

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“…Blood samples (60 ml) were obtained from healthy Caucasian volunteers by venopuncture, and PBMC were isolated as described previously (5). A total of 4 ϫ 10 6 cells per assay were resuspended in CellFIX for assessment of P-gp, CD4, CXCR4, and CCR5 expression by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

Functional Correlation of P-Glycoprotein Expression and Genotype with Expression of the Human Immunodeficiency Virus Type 1 Coreceptor CXCR4

Owen¹,

Chandler²,

Bray

et al. 2004

J Virol

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The aim of this study was to investigate the relationship between lymphocyte P-glycoprotein (P-gp) expression and genotype in vivo and the expression of lymphocyte receptors critical in the life cycle of human immunodeficiency virus type 1 (HIV-1), i.e., CD4, CCR5, and CXCR4. Using flow cytometry to quantify each membrane receptor/transporter, we demonstrate a highly significant correlation between P-gp protein expression and the expression of CXCR4 (rho ‫؍‬ 0.874; P < 0.0001). Furthermore, confocal microscopy showed colocalized expression of CXCR4 and P-gp in the lymphocyte membrane. This significant relationship was also apparent at the mRNA level by use of reverse transcription-PCR (rho ‫؍‬ 0.61; P < 0.005) and was present in both phytohemagglutinin-stimulated and unstimulated peripheral blood mononuclear cells. Genotypic analysis of the C3435T single-nucleotide polymorphism of P-gp confirmed significantly higher levels of P-gp in C (range, 2.45 to 11.00 relative fluorescence units [RFU])-than in T (range, 0.25 to 5.00 RFU)-homozygous individuals (P ‫؍‬ 0.0088; 95% confidence interval [95% CI], 0.7 to 6.3 RFU). An equivalent association between CXCR4 levels and C (range, 12.7 to 44.1 RFU) versus T (range, 3 to 18.9 RFU) genotype was also demonstrated (P ‫؍‬ 0.0019; 95% CI, 5.4 to 23.7). Functionally, although these correlates had no impact on HIV-1 production from either X4-or R5-tropic virus, expression correlated significantly with the activity of the HIV-1 protease inhibitor (PI) saquinavir for both P-gp (rho ‫؍‬ 0.75; P ‫؍‬ 0.0019) and CXCR4 (rho ‫؍‬ 0.71; P ‫؍‬ 0.0041). This study defines an association between P-gp (expression and genotype) and CXCR4 that may have implications for the selection of viral tropism and the access of drugs to protease for specific tropic types. The interplay between these two proteins may also influence the viral genotypes which escape effective chemotherapy and which therefore have the opportunity to evolve resistance to PIs.

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The Effects of Protease Inhibitors and Nonnucleoside Reverse Transcriptase Inhibitors on P-Glycoprotein Expression in Peripheral Blood Mononuclear Cells In Vitro

Cited by 87 publications

References 32 publications

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

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

Induction of Multiple Drug Transporters by Efavirenz

Functional Correlation of P-Glycoprotein Expression and Genotype with Expression of the Human Immunodeficiency Virus Type 1 Coreceptor CXCR4

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