HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Yuan, C.-S. Articles by Moss, J. Search for Related Content PubMed PubMed Citation Articles by Yuan, C.-S. Articles by Moss, J.

Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans

From the Committee on Clinical Pharmacology and Pharmacogenomics, Department of Anesthesia & Critical Care, and Department of Health Studies, Pritzker School of Medicine, University of Chicago, Chicago, Illinois; Progenics Pharmaceuticals Inc, Tarrytown, NY; and Piedmont Consulting Group LLP, Oakland, CA.

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.

Key Words: Methylnaltrexone • tolerability • safety • adverse effects • opioid bowel dysfunction • oral-cecal transit time • gut motility • subjective rating • pharmacokinetics • humans

Address for reprints: Chun-Su Yuan, MD, PhD, Department of Anesthesia & Critical Care, Pritzker School of Medicine, University of Chicago, 5841 S. Maryland Avenue, MC 4028, Chicago, IL 60637.

This article has been cited by other articles:

				P. A. Singleton, J. G.N. Garcia, and J. Moss Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor-induced angiogenesis Mol. Cancer Ther., June 1, 2008; 7(6): 1669 - 1679. [Abstract] [Full Text] [PDF]

				M. D. Kraft Emerging pharmacologic options for treating postoperative ileus Am. J. Health Syst. Pharm., October 15, 2007; 64(20_Supplement_13): S13 - S20. [Abstract] [Full Text] [PDF]

				P. A. Singleton, L. Moreno-Vinasco, S. Sammani, S. L. Wanderling, J. Moss, and J. G. N. Garcia Attenuation of Vascular Permeability by Methylnaltrexone: Role of mOP-R and S1P3 Transactivation Am. J. Respir. Cell Mol. Biol., August 1, 2007; 37(2): 222 - 231. [Abstract] [Full Text] [PDF]