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.