Assay for methylnaltrexone in rat brain regions and serum by high-performance liquid chromatography with coulometric electrochemical detection

Kim, C.; Cheng, Rihua; Corrigall, William A.; Coen, Kathleen M.

doi:10.1007/bf02261014

Cited by 22 publications

(9 citation statements)

References 11 publications

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“…Plasma and urine methylnaltrexone levels were determined by high-performance liquid chromatography technique using a previously reported method (Kim et al, 1989;Yuan et al, 1996). The practical limit of detection for plasma samples was approximately 2 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

Yuan¹,

Wei²,

Foss³

et al. 2002

J Pharmacol Exp Ther

111

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Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. However, the effects of subcutaneous methylnaltrexone, a more convenient route of administration, have not been evaluated. In this controlled trial, we evaluated the efficacy of subcutanous methylnaltrexone in antagonizing morphine-induced delay in oral-cecal transit time. In addition, opioid-induced unpleasant subjective effects and pharmacokinetics were studied. We observed that in the first group (n ϭ 6) morphine (0.05 mg/kg intravenously) increased the transit time from a baseline level of 85 Ϯ 20.5 min to 155 Ϯ 27.9 min (mean Ϯ S.D., P Ͻ 0.01). After 0.1 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 110 Ϯ 41.0 min. In the second group (n ϭ 6), morphine increased the transit time from a baseline level of 98 Ϯ 49.1 min to 140 Ϯ 58.2 min (P Ͻ 0.01). After 0.3 mg/kg subcutaneous methylnaltrexone plus morphine, the transit time reduced to 108 Ϯ 59.6 min (P Ͻ 0.05 compared with placebo plus morphine). In addition, subcutaneous methylnaltrexone significantly decreased morphineinduced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.

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Section: Methodsmentioning

confidence: 99%

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

Yuan¹,

Wei²,

Foss³

et al. 2002

J Pharmacol Exp Ther

111

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“…Significant amounts of the parent compound are also excreted unchanged in the urine . In our clinical pharmacology laboratory, we developed a sensitive plasma HPLC assay for methylnaltrexone and performed extensive pharmacokinetic studies in humans [Kim et al, 1989;Yuan et al, 1997].…”

Section: Data From Clinical Trialsmentioning

confidence: 99%

Methylnaltrexone: Investigation of clinical applications

Yuan

Foss

2000

Drug Dev. Res.

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Morphine and related opioids are widely used medications that are associated with a number of limiting side effects. In the last three decades significant progress has been achieved in our understanding of the mechanisms of action of these opioids; however, these advances have yielded few new approaches to the management of opioid side effects. Methylnaltrexone, the first peripheral opioid antagonist currently under clinical investigation, has the potential to prevent or treat opioid‐induced peripherally mediated side effects without interfering with analgesia. This article reviews data obtained from preclinical and clinical studies on methylnaltrexone that focus on the antagonism of opioid‐induced constipation. Other potential clinical applications of the compound are also discussed. Drug Dev. Res. 50:133–141, 2000. © 2000 Wiley‐Liss, Inc.

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“…A limited number of studies have examined the metabolism of MNTX in animals and humans (Misra et al, 1987;Kim et al, 1989;Kotake et al, 1989;Murphy et al, 2001). The focus of those studies was to evaluate the potential uptake into the brain in rats and the ABBREVIATIONS: MNTX, methylnaltrexone; HPLC, high-performance liquid chromatography; M2, MNTX-3-sulfate; LC/MS, liquid chromatography/mass spectrometry; M4, methyl-6␣-naltrexol; M5, methyl-6␤-naltrexol; AUC, area under curve; MS/MS, tandem mass spectrometry; 2D, two dimensional; M6, 2-hydroxy-3-O-methyl MNTX; M9, MNTX-3-glucuronide; M10, and 2-hydroxy-3-O-methyl MNTX glucuronide.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, MNTX treatment did not affect central analgesia or lead to opioid withdrawal (Thomas et al, 2008). Methylnaltrexone bromide (RELISTOR; Progenics Pharmaceuticals, Inc., Tarrytown, NY) is currently approved in the United States as an injectable medication for the treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient, and is approved elsewhere around the world for similar indications.A limited number of studies have examined the metabolism of MNTX in animals and humans (Misra et al, 1987;Kim et al, 1989;Kotake et al, 1989;Murphy et al, 2001). The focus of those studies was to evaluate the potential uptake into the brain in rats and the ABBREVIATIONS: MNTX, methylnaltrexone; HPLC, high-performance liquid chromatography; M2, MNTX-3-sulfate; LC/MS, liquid chromatography/mass spectrometry; M4, methyl-6␣-naltrexol; M5, methyl-6␤-naltrexol; AUC, area under curve; MS/MS, tandem mass spectrometry; 2D, two dimensional; M6, 2-hydroxy-3-O-methyl MNTX; M9, MNTX-3-glucuronide; M10, and 2-hydroxy-3-O-methyl MNTX glucuronide.…”

mentioning

confidence: 99%

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Metabolism of Intravenous Methylnaltrexone in Mice, Rats, Dogs, and Humans

Chandrasekaran¹,

Zheng²,

Li³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Methylnaltrexone (MNTX), a selective -opioid receptor antagonist, functions as a peripherally acting receptor antagonist in tissues of the gastrointestinal tract. This report describes the metabolic fate of [ 3 H]MNTX or [ 14 C]MNTX bromide in mice, rats, dogs, and humans after intravenous administration. Separation and identification of plasma and urinary MNTX metabolites was achieved by high-performance liquid chromatography-radioactivity detection and liquid chromatography/mass spectrometry. The structures of the most abundant human metabolites were confirmed by chemical synthesis and NMR spectroscopic analysis. Analysis of radioactivity in plasma and urine showed that MNTX underwent two major pathways of metabolism in humans: sulfation of the phenolic group to MNTX-3-sulfate (M2) and reduction of the carbonyl group to two epimeric alcohols, methyl-6␣-naltrexol (M4) and methyl-6␤-naltrexol (M5). Neither naltrexone nor its metabolite 6␤-naltrexol were detected in human plasma after administration of MNTX, confirming an earlier observation that N-demethylation was not a metabolic pathway of MNTX in humans. The urinary metabolite profiles in humans were consistent with plasma profiles. In mice, the circulating and urinary metabolites included M5, MNTX-3-glucuronide (M9), 2-hydroxy-3-O-methyl MNTX (M6), and its glucuronide (M10). M2, M5, M6, and M9 were observed in rats. Dogs produced only one metabolite, M9. In conclusion, MNTX was not extensively metabolized in humans. Conversion to methyl-6-naltrexol isomers (M4 and M5) and M2 were the primary pathways of metabolism in humans. MNTX was metabolized to a higher extent in mice than in rats, dogs, and humans. Glucuronidation was a major metabolic pathway in mice, rats, and dogs, but not in humans. Overall, the data suggested species differences in the metabolism of MNTX.Methylnaltrexone (MNTX) bromide [(5␣)-17-(cyclopropylmethyl)-3,14-dihydroxy-17-methyl-4,5-epoxymorphinanium-17-ium-6-one] is a selective peripherally acting -opioid receptor antagonist. In vitro testing shows that MNTX binds to receptors at 8-fold higher potency than to receptors, and it does not interact with ␦ receptors. MNTX is a quaternary derivative of the opioid antagonist naltrexone (Brown and Goldberg, 1985). The addition of the methyl group to naltrexone at the nitrogen atom forms MNTX, an inherently positively charged compound with greater polarity and lower lipid solubility than naltrexone. MNTX is restricted from crossing the blood-brain barrier in animals at pharmacologically relevant doses (Brown and Goldberg, 1985;Yuan et al., 1996Yuan et al., , 1998. MNTX prevents the inhibition of opioid-induced gut contractions in guinea pig ileum (Chen and Rosow, 2007). Studies in a variety of animal species have shown that peripherally or systemically administered MNTX blocks the peripherally mediated side effects of opioids, particularly their inhibition of gastrointestinal motility, with no effect on centrally mediated analgesia or opioid tolerance.MNTX reverses the opioid-induced del...

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Assay for methylnaltrexone in rat brain regions and serum by high-performance liquid chromatography with coulometric electrochemical detection

Cited by 22 publications

References 11 publications

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

Effects of Subcutaneous Methylnaltrexone on Morphine-Induced Peripherally Mediated Side Effects: A Double-Blind Randomized Placebo-Controlled Trial

Methylnaltrexone: Investigation of clinical applications

Metabolism of Intravenous Methylnaltrexone in Mice, Rats, Dogs, and Humans

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