title: Extended-release but not immediate-release and subcutaneous methylnaltrexone antagonizes the loperamide-induced delay of whole-gut transit time in healthy subjects.
abstract: Methylnaltrexone (MNTX) is approved for subcutaneous treatment (MNTX-SC) of opioid induced constipation. MNTX in oral immediate-release (MNTX-IR) and extended-release (MNTX-ER) dosage forms may antagonize the opioid induced delay in oro-cecal transit time (OCT) as measured by using radiolabeled lactulose. Because lactulose acts laxative by its own and efficacy of MNTX on colon transit time (CTT) was unknown, the opioid antagonistic effects MNTX-IR and MNTX-ER (both 500 mg) relative to MNTX-SC (12 mg) were evaluated in 15 healthy subjects with loperamide (LOP, 3 × 4 mg, 12 hourly) induced experimental constipation using the sulfasalazine/sulfapyridine method and radio-opaque markers to measure OCT and whole gut transit time (WGT). MNTX-ER significantly antagonized the LOP effects in 12 of our 15 subjects who responded to LOP with prolongation of WGT by 20.6-74.1 h (OCT by 0.50-10.5 h, CTT by 18.3-73.6 h). MNTX-SC and MNTX-IR were without significant influence. Compared to MNTX-SC, bioavailability of MNTX-IR and MNTX-ER was 1.53-5.49% and 0.11-1.24%, respectively. MNTX-SC and MNTX-IR achieved active serum levels only for ∼ 3-5 h. MNTX-ER antagonized the opioid-induced delay of CTT most likely by local effects on µ-opioid receptors in the colon.
authors: Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany.
authors: Julia
authors: J
authors: Kolbow
authors: Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany.
authors: Christiane
authors: C
authors: Modess
authors: Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany.
authors: Danilo
authors: D
authors: Wegner
authors: Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany.
authors: Stefan
authors: S
authors: Oswald
authors: Develco Pharma Schweiz AG, Pratteln, Switzerland.
authors: Martina Alice
authors: MA
authors: Maritz
authors: Develco Pharma Schweiz AG, Pratteln, Switzerland.
authors: Hélène
authors: H
authors: Rey
authors: Department of Pharmaceutical Technology and Biopharmacy, Center of Drug Absorption and Transport, University of Greifswald, Greifswald, Germany.
authors: Werner
authors: W
authors: Weitschies
authors: Department of Clinical Pharmacology, Center of Drug Absorption and Transport, University Medicine, Greifswald, Germany.
authors: Werner
authors: W
authors: Siegmund
mesh_terms: D000328:Adult; D000930:Antidiarrheals / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D003248:Constipation / Q000139:chemically induced / Q000188:drug therapy; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D007279:Injections, Subcutaneous; D008139:Loperamide / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000930:Antidiarrheals; D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009271:Naltrexone; D008139:Loperamide
keywords: experimental constipation; extended release; loperamide; methylnaltrexone