1. ¹Clinical Research Services Turku (CRST), University of Turku, Turku, Finland
2. ²Turku PET Centre, University of Turku, Turku, Finland
3. ³Biotie Therapies Corp., Turku, Finland
4. ⁴Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland
5. ⁵Department of Anaesthesiology and Intensive Care, Turku University Central Hospital and University of Turku, Turku, Finland
6. ⁶Department of Psychiatry, University of Turku, Turku, Finland

Correspondence: Professor H Scheinin, Turku PET Centre, University of Turku, PO Box 52, FIN-20521 Turku, Finland. Tel: +358 2 313 1870; Fax: +358 2 231 8191; E-mail: harry.scheinin@utu.fi

Received 30 December 2004; Revised 29 April 2005; Accepted 29 April 2005; Published online 8 June 2005.

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 -opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and -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 -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 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 -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 -opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from -opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high -opioid receptor occupancy can be maintained when nalmefene is taken once daily.