Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells

Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of bloo...

Full description

Saved in:
Bibliographic Details
Published in:Journal of pharmacy and pharmacology 2007-07, Vol.59 (7), p.947-953
Main Authors: Perloff, Michael D., von Moltke, Lisa L., Fahey, Jeanne M., Greenblatt, David J.
Format: Article
Language:English
Subjects:
Animals
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Blood-Brain Barrier - metabolism
Blotting, Western
Brain - blood supply
Cattle
Cells, Cultured
Endothelium, Vascular - metabolism
HIV Protease Inhibitors - adverse effects
Human immunodeficiency virus
Ritonavir - adverse effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413
cites cdi_FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413
container_end_page 953
container_issue 7
container_start_page 947
container_title Journal of pharmacy and pharmacology
container_volume 59
creator Perloff, Michael D.
von Moltke, Lisa L.
Fahey, Jeanne M.
Greenblatt, David J.
description Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood‐brain barrier (BBB) drug transporters (P‐glycoprotein; P‐gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in‐vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P‐gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co‐incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P‐gp activity. P‐gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P‐gp immunoreactive protein in a concentration‐dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 μM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P‐gp protein increased 2‐fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P‐gp immunoreactive protein was observed (Spearman r2 = 0.77, P < 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration‐dependent increase in P‐gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.
doi_str_mv 10.1211/jpp.59.7.0006
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_20073728</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>20073728</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413</originalsourceid><addsrcrecordid>eNp9kEtP3DAURi3Uqkxpl2yRV91l6kfixxIhGECUTqUi2FlOctMaMnawMwP59_VoRrDr6sryuZ--exA6pmROGaXfH4dhXum5nBNCxAGaMVKyQtJKfUAzQhgreCX5Ifqc0mMmpBDiEzqkUnBJlZ4hf-XbdTO64HHo8LL4009NGGIYwXkMr0OElLaf1rfYZm7jxgnXE45uDN5uXMSZq8PGecB1tPmxck0Mm7wGPQbfhvEv9M72uIG-T1_Qx872Cb7u5xG6uzj_fXZZ3PxcXJ2d3hRNKQkvpNDctly1qgIGogRVqjwqIZRWnc2MbmutlQXFteSW1pQypUnNqq6VJeVH6NsuN5_yvIY0mpVL2wbWQ1gnw7IKLpnKYLEDc-mUInRmiG5l42QoMVvBJgs2lTbSbAVn_mQfvK5X0L7Te6MZ4DvgxfUw_T_NXC8vl5RL_l7DpRFe37ZsfDIiF63M_e3C3F8vFg_y1w8j-T9cgpdY</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20073728</pqid></control><display><type>article</type><title>Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells</title><source>Wiley</source><source>Oxford Journals - Connect here FIRST to enable access</source><creator>Perloff, Michael D. ; von Moltke, Lisa L. ; Fahey, Jeanne M. ; Greenblatt, David J.</creator><creatorcontrib>Perloff, Michael D. ; von Moltke, Lisa L. ; Fahey, Jeanne M. ; Greenblatt, David J.</creatorcontrib><description>Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood‐brain barrier (BBB) drug transporters (P‐glycoprotein; P‐gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in‐vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P‐gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co‐incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P‐gp activity. P‐gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P‐gp immunoreactive protein in a concentration‐dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 μM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P‐gp protein increased 2‐fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P‐gp immunoreactive protein was observed (Spearman r2 = 0.77, P &lt; 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration‐dependent increase in P‐gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.</description><identifier>ISSN: 0022-3573</identifier><identifier>EISSN: 2042-7158</identifier><identifier>DOI: 10.1211/jpp.59.7.0006</identifier><identifier>PMID: 17637189</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis ; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism ; Blood-Brain Barrier - metabolism ; Blotting, Western ; Brain - blood supply ; Cattle ; Cells, Cultured ; Endothelium, Vascular - metabolism ; HIV Protease Inhibitors - adverse effects ; Human immunodeficiency virus ; Ritonavir - adverse effects</subject><ispartof>Journal of pharmacy and pharmacology, 2007-07, Vol.59 (7), p.947-953</ispartof><rights>2007 Royal Pharmaceutical Society of Great Britain</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413</citedby><cites>FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1211%2Fjpp.59.7.0006$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1211%2Fjpp.59.7.0006$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,786,790,27957,27958,50923,51032</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17637189$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Perloff, Michael D.</creatorcontrib><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Fahey, Jeanne M.</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><title>Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells</title><title>Journal of pharmacy and pharmacology</title><addtitle>J Pharm Pharmacol</addtitle><description>Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood‐brain barrier (BBB) drug transporters (P‐glycoprotein; P‐gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in‐vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P‐gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co‐incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P‐gp activity. P‐gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P‐gp immunoreactive protein in a concentration‐dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 μM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P‐gp protein increased 2‐fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P‐gp immunoreactive protein was observed (Spearman r2 = 0.77, P &lt; 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration‐dependent increase in P‐gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.</description><subject>Animals</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis</subject><subject>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Blotting, Western</subject><subject>Brain - blood supply</subject><subject>Cattle</subject><subject>Cells, Cultured</subject><subject>Endothelium, Vascular - metabolism</subject><subject>HIV Protease Inhibitors - adverse effects</subject><subject>Human immunodeficiency virus</subject><subject>Ritonavir - adverse effects</subject><issn>0022-3573</issn><issn>2042-7158</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNp9kEtP3DAURi3Uqkxpl2yRV91l6kfixxIhGECUTqUi2FlOctMaMnawMwP59_VoRrDr6sryuZ--exA6pmROGaXfH4dhXum5nBNCxAGaMVKyQtJKfUAzQhgreCX5Ifqc0mMmpBDiEzqkUnBJlZ4hf-XbdTO64HHo8LL4009NGGIYwXkMr0OElLaf1rfYZm7jxgnXE45uDN5uXMSZq8PGecB1tPmxck0Mm7wGPQbfhvEv9M72uIG-T1_Qx872Cb7u5xG6uzj_fXZZ3PxcXJ2d3hRNKQkvpNDctly1qgIGogRVqjwqIZRWnc2MbmutlQXFteSW1pQypUnNqq6VJeVH6NsuN5_yvIY0mpVL2wbWQ1gnw7IKLpnKYLEDc-mUInRmiG5l42QoMVvBJgs2lTbSbAVn_mQfvK5X0L7Te6MZ4DvgxfUw_T_NXC8vl5RL_l7DpRFe37ZsfDIiF63M_e3C3F8vFg_y1w8j-T9cgpdY</recordid><startdate>200707</startdate><enddate>200707</enddate><creator>Perloff, Michael D.</creator><creator>von Moltke, Lisa L.</creator><creator>Fahey, Jeanne M.</creator><creator>Greenblatt, David J.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>200707</creationdate><title>Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells</title><author>Perloff, Michael D. ; von Moltke, Lisa L. ; Fahey, Jeanne M. ; Greenblatt, David J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis</topic><topic>ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Blotting, Western</topic><topic>Brain - blood supply</topic><topic>Cattle</topic><topic>Cells, Cultured</topic><topic>Endothelium, Vascular - metabolism</topic><topic>HIV Protease Inhibitors - adverse effects</topic><topic>Human immunodeficiency virus</topic><topic>Ritonavir - adverse effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perloff, Michael D.</creatorcontrib><creatorcontrib>von Moltke, Lisa L.</creatorcontrib><creatorcontrib>Fahey, Jeanne M.</creatorcontrib><creatorcontrib>Greenblatt, David J.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Journal of pharmacy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Perloff, Michael D.</au><au>von Moltke, Lisa L.</au><au>Fahey, Jeanne M.</au><au>Greenblatt, David J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells</atitle><jtitle>Journal of pharmacy and pharmacology</jtitle><addtitle>J Pharm Pharmacol</addtitle><date>2007-07</date><risdate>2007</risdate><volume>59</volume><issue>7</issue><spage>947</spage><epage>953</epage><pages>947-953</pages><issn>0022-3573</issn><eissn>2042-7158</eissn><notes>istex:CFF0F4BB0FFF1EE60A380302376C607ECA655534</notes><notes>ark:/67375/WNG-WJGGX7QM-7</notes><notes>ArticleID:JPHP1373</notes><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood‐brain barrier (BBB) drug transporters (P‐glycoprotein; P‐gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in‐vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P‐gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co‐incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P‐gp activity. P‐gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P‐gp immunoreactive protein in a concentration‐dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 μM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P‐gp protein increased 2‐fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P‐gp immunoreactive protein was observed (Spearman r2 = 0.77, P &lt; 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration‐dependent increase in P‐gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>17637189</pmid><doi>10.1211/jpp.59.7.0006</doi><tpages>7</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0022-3573
ispartof Journal of pharmacy and pharmacology, 2007-07, Vol.59 (7), p.947-953
issn 0022-3573
2042-7158
language eng
recordid cdi_proquest_miscellaneous_20073728
source Wiley; Oxford Journals - Connect here FIRST to enable access
subjects Animals
ATP-Binding Cassette, Sub-Family B, Member 1 - biosynthesis
ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism
Blood-Brain Barrier - metabolism
Blotting, Western
Brain - blood supply
Cattle
Cells, Cultured
Endothelium, Vascular - metabolism
HIV Protease Inhibitors - adverse effects
Human immunodeficiency virus
Ritonavir - adverse effects
title Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-23T05%3A24%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Induction%20of%20P-glycoprotein%20expression%20and%20activity%20by%20ritonavir%20in%20bovine%20brain%20microvessel%20endothelial%20cells&rft.jtitle=Journal%20of%20pharmacy%20and%20pharmacology&rft.au=Perloff,%20Michael%20D.&rft.date=2007-07&rft.volume=59&rft.issue=7&rft.spage=947&rft.epage=953&rft.pages=947-953&rft.issn=0022-3573&rft.eissn=2042-7158&rft_id=info:doi/10.1211/jpp.59.7.0006&rft_dat=%3Cproquest_cross%3E20073728%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c4703-7693ad38d85e2e64e848e64566898fa4709db998ae83973a1b112890b25fd7413%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=20073728&rft_id=info:pmid/17637189&rfr_iscdi=true