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- Title
Prolonged Central μ-Opioid Receptor Occupancy after Single and Repeated Nalmefene Dosing.
- Authors
Ingman, Kimmo; Hagelberg, Nora; Aalto, Sargo; Någren, Kjell; Juhakoski, Auni; Karhuvaara, Sakari; Kallio, Antero; Oikonen, Vesa; Hietala, Jarmo; Scheinin, Harry
- 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 μ-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and μ-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 μ-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [11C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t1/2 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 μ-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 μ-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from μ-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high μ-opioid receptor occupancy can be maintained when nalmefene is taken once daily.Neuropsychopharmacology (2005) 30, 2245–2253. doi:10.1038/sj.npp.1300790; published online 8 June 2005
- Subjects
PHARMACODYNAMICS; OPIOID receptors; ALCOHOLISM treatment; ANTIDEPRESSANTS; ANTIPSYCHOTIC agents; DRUG metabolism; SUBSTANCE abuse treatment; NEUROPSYCHOPHARMACOLOGY
- Publication
Neuropsychopharmacology, 2005, Vol 30, Issue 12, p2245
- ISSN
0893-133X
- Publication type
Article
- DOI
10.1038/sj.npp.1300790