Yuan Chun-Su, Doshan Harold, Charney Martha R, O'connor Michael, Karrison Theodore, Maleckar S A, Israel Robert J, Moss Jonathan
Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC 4028, Chicago, IL 60637, USA.
J Clin Pharmacol. 2005 May;45(5):538-46. doi: 10.1177/0091270004273491.
Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.
以往研究表明，单剂量甲基纳曲酮（一种独特的外周阿片类拮抗剂）可逆转阿片类药物引起的人体肠道运动功能减退。由于治疗阿片类药物引起的或术后肠道功能障碍的患者可能需要重复给药，因此作者现在研究了甲基纳曲酮多剂量方案的安全性、药理活性和药代动力学，该方案以连续12次静脉给药（每6小时0.3mg/kg）的方式给予12名健康受试者。稳态迅速达到，在重复给药3天后，甲基纳曲酮将口服至盲肠转运时间从预处理基线值101.3±29.4分钟（平均值±标准差）降至82.5±20.7分钟。给药后5分钟测得的最大观察血浆浓度，第1剂和第2剂后分别为538±237和675±180ng/mL。基于6小时采样期，第1剂和第12剂后的血浆半衰期分别为2.5±0.5和2.9±0.9小时，在稳态时未发生变化。根据第12剂和第1剂后AUC值的比值，甲基纳曲酮基本没有蓄积。这项研究表明，静脉注射甲基纳曲酮在人体中重复给药耐受性良好，没有明显的不良事件或阿片类主观评分变化，药代动力学也没有临床上值得注意的改变。对这些未使用过阿片类药物的志愿者重复给予甲基纳曲酮后肠道转运时间显著缩短，这一观察结果表明内源性阿片类物质调节人体肠道运动。
