title: Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing.
abstract: The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central mu-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and mu-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central mu-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [(11)C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t(1/2) of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at mu-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged mu-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from mu-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high mu-opioid receptor occupancy can be maintained when nalmefene is taken once daily.
authors.affiliation: Clinical Research Services Turku (CRST), University of Turku, FIN-20521 Turku, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Ingman
authors.forename: Nora
authors.initials: N
authors.lastname: Hagelberg
authors.forename: Sargo
authors.initials: S
authors.lastname: Aalto
authors.forename: Kjell
authors.initials: K
authors.lastname: Någren
authors.forename: Auni
authors.initials: A
authors.lastname: Juhakoski
authors.forename: Sakari
authors.initials: S
authors.lastname: Karhuvaara
authors.forename: Antero
authors.initials: A
authors.lastname: Kallio
authors.forename: Vesa
authors.initials: V
authors.lastname: Oikonen
authors.forename: Jarmo
authors.initials: J
authors.lastname: Hietala
authors.forename: Harry
authors.initials: H
authors.lastname: Scheinin
mesh_terms: D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid / Q000493:pharmacokinetics; D019540:Area Under Curve; D002421:Caudate Nucleus / Q000378:metabolism; D004562:Electrocardiography / Q000187:drug effects; D005283:Fentanyl / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009292:Narcotic Antagonists / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D017397:Prefrontal Cortex / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013788:Thalamus / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D020719:Glucuronides; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D009271:Naltrexone; C017114:carfentanil; C038981:nalmefene; D005283:Fentanyl