This study was performed to develop an integrated pharmacokinetic-pharmacodynamic model for estimating the contribution of morphine-6-glucuronide (M6G) to morphine-associated antinociception in humans. Healthy volunteers (n = 8) received 10 mg of morphine sulfate as a 5-minute i.v. infusion. A Contact Thermode heat probe was placed on the volar forearm to elicitpain. 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- and effect-time data were analyzed by stepwise nonlinear least-squares regression. The pharmacodynamic parameter estimates were recovered with a linear effect-compartment model and were used to assess the contribution of M6G to morphine-associated analgesia. The estimates (mean +/- SEM) for morphine total clearance and steady-state volume of distribution were 1.0 +/- 0.07 L/h/kg and 1.6 +/- 0.1 L/kg, respectively. The AUC ratio of M6G to morphine was 0.73 +/- 0.06. The contribution of M6G to analgesia ranged from < 0.1% to 66% and was inversely related to the overall effect elicited by the morphine dose (r2 = 0.776). Differences in gender were observed where the contribution (mean +/- SEM) of M6G to analgesia was 32% +/- 19% in males (n = 3) and 13% +/- 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.

译文

进行这项研究是为了开发一种综合的药代动力学-药效学模型,用于估计morphine-6-glucuronide (M6G) 对人类吗啡相关抗伤害感受的贡献。健康志愿者 (n = 8) 接受10毫克硫酸吗啡5分钟静脉输注。将接触式热模热探针放在前臂上,以引起疼痛。在8小时内以固定的时间间隔测量热阈值 (定义为首次感觉到疼痛的温度)。通过LC/MS测定吗啡和M6G的血清浓度。通过逐步非线性最小二乘回归分析浓度和效应时间数据。用线性效应室模型恢复药效学参数估计值,并用于评估M6G对吗啡相关镇痛的贡献。吗啡总清除率和稳态分布体积的估计值 (平均值/- SEM) 分别为1.0/- 0.07 L/h/kg和1.6/- 0.1 L/kg。M6G与吗啡的AUC比为0.73 +/- 0.06。M6G对镇痛的贡献范围为 <0.1% 至66%,并且与吗啡剂量引起的总体效果成反比 (r2 = 0.776)。观察到性别差异,其中M6G对镇痛的贡献 (平均/- SEM) 在男性 (n = 3) 中32%/- 19%,在女性 (n = 5) 中13%/- 8%。这些结果表明,随着吗啡的总体作用增加,M6G的分数贡献下降,而M6G对镇痛的贡献在男性和女性之间可能有所不同。M6G/吗啡系统的改变可能具有临床上显着的药效学后果。

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