{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:38:59Z","timestamp":1790865539118,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2007,12,18]],"date-time":"2007-12-18T00:00:00Z","timestamp":1197936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:sec><jats:label\/><jats:p><jats:bold>WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT<\/jats:bold><\/jats:p><jats:p>\u2022\u2003We have shown previously using the dually perfused isolated human placenta model that the maternal to foetal transfer of the antiviral protease inhibitor drug indinavir is substantially lower than the transfer in the opposite direction.<\/jats:p><jats:p>\u2022\u2003This finding is not consistent with passive diffusion and indicates that a carrier\u2010mediated mechanism is involved in retarding the movement in the maternal to foetal direction.<\/jats:p><jats:p>\u2022\u2003The efflux transporter P\u2010gp located in the apical membrane domain of the placental trophoblast cells has been implicated as the likely cause of the differential bi\u2010directional transport.<\/jats:p><jats:p><jats:bold>WHAT THIS STUDY ADDS<\/jats:bold><\/jats:p><jats:p>\u2022\u2003The present study also utilizes the human perfused human isolated placenta to investigate the possible inhibitory effects of the P\u2010gp inhibitor PSC833 and the P\u2010gp substrate\/inhibitor ritonavir on the maternal to foetal transfer clearance of indinavir.<\/jats:p><jats:p>\u2022\u2003The studies, which were conducted such that each placenta served as its own control, demonstrated a statistically significant increase in the maternal to foetal transfer of indinavir in the presence of PSC833 but not in the presence of ritonavir, a protease inhibitor that is often used in combination with other protease inhibitors in dual therapy.<\/jats:p><jats:p>\u2022\u2003The lack of effect of ritonavir is most likely related to the relatively low inhibitory activity at the clinically relevant concentration used in this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>AIMS<\/jats:title><jats:p>To investigate the effect of P\u2010gp inhibition on the maternal to foetal transfer of indinavir.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Term human placentae (<jats:italic>n<\/jats:italic>\u2003=\u200312) were from non\u2010HIV infected women. Maternal to foetal transfer of indinavir was examined in the absence and presence of P\u2010gp inhibitors PSC833 (<jats:italic>n<\/jats:italic>\u2003=\u20037) or ritonavir (<jats:italic>n<\/jats:italic>\u2003=\u20035), in the perfused human placenta. Antipyrine and [<jats:sup>3<\/jats:sup>H]\u2010vinblastine were included as markers of passive diffusion and P\u2010gp transport, respectively. These markers and indinavir were added to maternal perfusate at 0\u2003min; PSC833 or ritonavir was added at 25\u2003min. Steady\u2010state maternal to foetal transfer clearance was calculated during control and inhibitor phases. Indinavir and vinblastine clearances were normalized to antipyrine clearance (clearance index).<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>Indinavir clearance index increased between the control (0.25\u2003\u00b1\u20030.03) and PSC833 phases (0.37\u2003\u00b1\u20030.14) (95% CI of the difference \u22120.23, \u22120.002). Vinblastine clearance index increased from (0.25\u2003\u00b1\u20030.08) to (0.34\u2003\u00b1\u20030.06) in the control and PSC833 phases, respectively (95% CI of difference \u22120.14, \u22120.05). Indinavir clearance index was unchanged between control (0.34\u2003\u00b1\u20030.14) and ritonavir phases (0.39\u2003\u00b1\u20030.13) (95% CI of the difference \u22120.19, 0.08). Vinblastine clearance index increased from (0.24\u2003\u00b1\u20030.12) to (0.32\u2003\u00b1\u20030.12) in the control and ritonavir phases, respectively (95% CI of the difference \u22120.15, \u22120.009).<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Maternal to foetal transfer clearance of indinavir and vinblastine increased following P\u2010gp inhibition. The potential role for co\u2010administration of P\u2010gp inhibitors with PIs to reduce perinatal HIV transmission warrants further investigation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1365-2125.2007.03067.x","type":"journal-article","created":{"date-parts":[[2008,4,10]],"date-time":"2008-04-10T16:43:51Z","timestamp":1207845831000},"page":"667-673","source":"Crossref","is-referenced-by-count":35,"title":["Inhibition of placental P\u2010glycoprotein: impact on indinavir transfer to the foetus"],"prefix":"10.1111","volume":"65","author":[{"given":"Sreeja","family":"Sudhakaran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig R.","family":"Rayner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C. M.","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil M.","family":"Gude","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger L.","family":"Nation","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,12,18]]},"reference":[{"key":"e_1_2_6_2_2","unstructured":"Public Health Service Task Force Perinatal HIVGWG.Recommendations for use of antiretroviral drugs in pregnant HIV\u20101 infected women for maternal health and interventions to reduce perinatal HIV\u20101 transmission in United States. October 12 2006 1\u201365. Available athttp:\/\/aidsinfo.nih.gov\/ContentFiles\/PerinatalGL.pdf(last accessed 15 September 2007)."},{"key":"e_1_2_6_3_2","unstructured":"UNAIDS.AIDS epidemic update 2004. Joint United Nations Program on HIV\/AIDS 2004."},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI7963"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200002180-00005"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2005.02.002"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(98)70078-X"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2006.01.017"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-0997(1998)6:6<244::AID-IDOG4>3.0.CO;2-B"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2001.113319"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2005.04.014"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.3.1023-1028.2005"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2005.02.023"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi972709x"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI1269"},{"key":"e_1_2_6_16_2","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0090-9556(24)15144-6","article-title":"Pharmacological inhibition of P\u2010glycoprotein transport enhances the distribution of HIV\u20101 protease inhibitors into brain and testes","volume":"28","author":"Choo EF","year":"2000","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-2952(99)00026-X"},{"key":"e_1_2_6_18_2","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1016\/S0090-9556(24)15186-0","article-title":"The disposition of saquinavir in normal and P\u2010glycoprotein deficient mice, rats, and in cultured cells","volume":"28","author":"Washington CB","year":"2000","journal-title":"Drug Metab Dispos"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200006160-00016"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4004(81)80018-5"},{"key":"e_1_2_6_21_2","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1159\/000410678","article-title":"Effect of flow rate ratio on the diffusion of antipyrine and 3H2O in the isolated dually in vitro perfused lobe of the human placenta","volume":"13","author":"Schneider H","year":"1985","journal-title":"Contrib Gynecol Obstet"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00743-3"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.9.3226-3232.2004"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2001.19.6.1589"},{"key":"e_1_2_6_25_2","unstructured":"Abbott Laboratories. North Chicago Illinois Norvir\u00ae Product Information May 2007."},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(91)90499-6"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-005-5271-y"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-6238(00)00071-X"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.4.806"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002030-200211220-00009"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.21013"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.065342"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113.11.2011"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0145-2126(96)00023-9"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)00327-9"},{"key":"e_1_2_6_36_2","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/S0022-3565(24)29643-9","article-title":"Expression of P\u2010glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR) \u20101 gene","volume":"297","author":"Tanabe M","year":"2001","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-200405000-00006"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.08.001"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1365-2125.2007.03067.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1365-2125.2007.03067.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T16:16:50Z","timestamp":1738167410000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/j.1365-2125.2007.03067.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,12,18]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008,5]]}},"alternative-id":["10.1111\/j.1365-2125.2007.03067.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1365-2125.2007.03067.x","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,12,18]]}}}