{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T19:59:54Z","timestamp":1769975994213,"version":"3.49.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,3,8]],"date-time":"2013-03-08T00:00:00Z","timestamp":1362700800000},"content-version":"vor","delay-in-days":3964,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2002,5]]},"abstract":"<jats:p>This study was performed to develop an integrated pharmacokinetic\u2010pharmacodynamic model for estimating the contribution of morphine\u20106\u2010glucuronide (M6G) to morphine\u2010associated antinociception in humans. Healthy volunteers (n = 8) received 10 mg of morphine sulfate as a 5\u2010minute IV infusion. A Contact Thermode\u00ae heat probe was placed on the volar forearm to elicit pain. Thermal threshold, defined as the temperature at which pain was first perceived, was measured at fixed time intervals over 8 hours. Serum concentrations of morphine and M6G were determined by LC\/MS. Concentration\u2010 and effect\u2010time data were analyzed by stepwise nonlinear least\u2010squares regression. The pharmacodynamic parameter estimates were recovered with a linear effect\u2010compartment model and were used to assess the contribution of M6G to morphine\u2010associated analgesia. The estimates (mean \u00b1 SEM) <jats:italic>for morphine total clearance and steady\u2010state volume of distribution were 1.0 \u00b1 0.07 L\/h\/kg and 1.6 \u00b1 0.1 L\/kg, respectively. The AUC ratio of M6G to morphine was 0.73 \u00b1 0.06. The contribution of M6G to an\u2010algesia ranged from &lt; 0.1% to 66% and was inversely related to the overall effect elicited by the morphine dose<\/jats:italic> (r<jats:sup>2<\/jats:sup> = <jats:italic>0.776). Differences in gender were observed where the contribution (mean<\/jats:italic> \u00b1 SEM) <jats:italic>of M6G to analgesia was 32% \u00b1 19% in males<\/jats:italic> (n = 3) and 13% \u00b1 8% in females (n = 5). These results suggest that as the overall effect of morphine increases, the fractional contribution of M6G declines and the contribution of M6G to analgesia may differ between males and females. Alterations in the M6G\/morphine system may have clinically significant pharmacodynamic consequences.<\/jats:p>","DOI":"10.1177\/00912700222011508","type":"journal-article","created":{"date-parts":[[2003,7,19]],"date-time":"2003-07-19T09:38:13Z","timestamp":1058607493000},"page":"569-576","source":"Crossref","is-referenced-by-count":69,"title":["Contribution of Morphine\u20106\u2010Glucuronide to Antinociception following Intravenous Administration of Morphine to Healthy Volunteers"],"prefix":"10.1002","volume":"42","author":[{"given":"Bindu P.","family":"Murthy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary M.","family":"Pollack","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim L. 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