{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T23:35:56Z","timestamp":1791070556932,"version":"4.1.0"},"reference-count":0,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2001,12,24]],"date-time":"2001-12-24T00:00:00Z","timestamp":1009152000000},"content-version":"vor","delay-in-days":479,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2000,9]]},"abstract":"<jats:p> <jats:bold>\n            <jats:italic>Aims<\/jats:italic>\n          <\/jats:bold> To investigate the effect of acute P\u2010glycoprotein inhibition by the multidrug\u2010resistance (MDR) modulator valspodar (SDZ PSC 833; PSC) on the pharmacokinetics, and potentially adverse pharmacodynamic effects of morphine, and its principal pharmacologically active metabolites, morphine\u20103\u2010glucuronide (M3G) and morphine\u20106\u2010glucuronide (M6G).<\/jats:p><jats:p> <jats:bold>\n            <jats:italic>Methods<\/jats:italic>\n          <\/jats:bold> In a double\u2010blind, three\u2010way crossover study, the pharmacokinetic and potentially adverse pharmacodynamic effects (reaction time, transcutaneous PCO<jats:sub>2<\/jats:sub>, blood pressure) of morphine were compared with and without acute inhibition ofP\u2010glycoprotein by PSC. The effects of PSC alone were also evaluated. The study was performed in 18\u2003healthy male volunteers and pharmacodynamic effects analysed by measuring the area under the effect (AUE) curve. 150\u2003mg PSC (or its placebo) was given as an i.v. infusion over 2\u2003h. With the expected inhibition of Pgp 1\u2003h after starting PSC infusion, 7.5 morphine HCl (or its placebo) was infused over 2\u2003h.<\/jats:p><jats:p> <jats:bold>\n            <jats:italic>Results<\/jats:italic>\n          <\/jats:bold> The infusion of PSC resulted in blood concentrations expected to inhibit Pgp mediated transport. While the pharmacokinetics of plasma morphine and M6G. were unaffected there was a small but statistically significant increase in the AUC and <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> of M3G (11.8 and 8.3%, respectively). The <jats:italic>t<\/jats:italic><jats:sub>\u00bd<\/jats:sub> and <jats:italic>t<\/jats:italic><jats:sub>max<\/jats:sub> were unaffected. The pharmacokinetic parameters of PSC were not affected by coadministration with morphine. PSC did not significantly affect the adverse events of morphine, as assessed by spontaneous reporting. Compared with PSC alone, morphine elicited an increase in reaction time (E<jats:sub>max<\/jats:sub> 48\u2003ms, compared with the predose absolute reaction time of 644\u2003ms), which was not detected by the alertness\u2010drowsiness score, indicating only slight sedation. There was a significant decrease in systolic blood pressure (E<jats:sub>min<\/jats:sub>\u22129\u2003mmHg), and a trend for a fall in diastolic blood pressure (E<jats:sub>min<\/jats:sub>\u221214.5\u2003mmHg) and respiratory rate (E<jats:sub>min<\/jats:sub>\u22121.8 breath\u00b7min<jats:sup>\u22121<\/jats:sup>). For all these parameters, the effects of PSC\/morphine were similar to that of PSC alone, suggesting some attenuation of morphine's effect. In contrast, morphine caused a significant increase in PCO<jats:sub>2<\/jats:sub> (E<jats:sub>max<\/jats:sub> 0.69\u2003kPa) compared to PSC alone, indicating slight respiratory depression. This increase was similar to that of the PSC\/morphine combination.<\/jats:p><jats:p> <jats:bold>\n            <jats:italic>Conclusions<\/jats:italic>\n          <\/jats:bold> Acute inhibition of P\u2010glycoprotein by PSC in this setting does not affect the pharmacokinetic or safety\u2010related pharmacodynamic profile of morphine in a clinically significant manner.<\/jats:p>","DOI":"10.1046\/j.1365-2125.2000.00226.x","type":"journal-article","created":{"date-parts":[[2003,3,11]],"date-time":"2003-03-11T04:39:29Z","timestamp":1047357569000},"page":"237-246","source":"Crossref","is-referenced-by-count":66,"title":["Effect of P\u2010glycoprotein modulation on the clinical pharmacokinetics and adverse effects of morphine"],"prefix":"10.1111","volume":"50","author":[{"given":"J\u00fcrgen","family":"Drewe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard A.","family":"Ball","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Beglinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kemmler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut","family":"Sch\u00e4chinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter E.","family":"Haefeli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2001,12,24]]},"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2125.2000.00226.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1046%2Fj.1365-2125.2000.00226.x","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1046\/j.1365-2125.2000.00226.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,29]],"date-time":"2023-10-29T14:25:16Z","timestamp":1698589516000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1046\/j.1365-2125.2000.00226.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,9]]},"references-count":0,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2000,9]]}},"alternative-id":["10.1046\/j.1365-2125.2000.00226.x"],"URL":"https:\/\/doi.org\/10.1046\/j.1365-2125.2000.00226.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":[[2000,9]]}}}