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

Comparative molecular field analysis (CoMFA) has been used as a three-dimensional quantitative structure-activity relationship (QSAR) method to correlate three different types of biological activity data with physicochemical properties of some clodronate ester analogues, which act as bone-resorption regulators in cell cultures and rats. The QSAR studies show the importance of the steric properties of these new bisphosphonate derivatives for the inhibition of bone resorption in bone cell cultures and for their bioavailability in rats. This information will be used in predicting the structure of new more potent bisphosphonic compounds.

Ahstyuct; Oxybutynin has an extensive first pass metabolism after oral administration. the main active metabolite being N-desethyloxybutynin. The purpose of this study was to investigate the CYP isoform specificity of oxybutynin N-deethylation and possible interactions. Oxybutynin N-deethylation in human liver microsomes in vifro was potently inhibited by ketoconazole (ICso 4.5 pM), less and variably by itraconazole and not by quinidine or several other reference inhibitors, suggesting that CYP3A enzymes are predominant catalysts of the reaction. Recombinant CYP3A5 enzyme had higher activity in oxybutynin N-deethylation than recombinant CYP3A4. Ketoconazole inhibited oxybutynin N-deethylation by the recombinant CYP3A4 and CYP3A5 almost completely, whereas itraconazole inhibited the activity of CYP3A4 more potently than that of CYP3A5. Oxybutynin inhibited CYP3A4-and CYP2D6-associated activities (testosterone 68-hydroxylase and dextromethorphan 0-demethylase. respectively) in human liver microsomes. CYPl A l/2-, CYPZAh-, CYP2C9-and CYPZEI-associated activities were inhibited less potently or not at all by oxybutynin when compared with reference inhibitors. Although the reasons for the weak and variable inhibition by itraconazole remain to be studied. it seems that oxybutynin is predominantly metabolized by CYP3A4 and CYP3A5 hut not by CYP2D6. However, it seems to have some affinity also to the latter enzyme.

Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.

Abstracl:The effect of time interval between food and drug ingestion on the bioavailability of oxybutynin was investigated in a randomized, three-phase cross-over study in 3 1 healthy volunteers. The serum concentrations of oxybutynin and the metabolite, N-desethyloxybutynin were measured up to 48 hr after ingestion of a controlled-release 10 mg oxybutynin tablet either in fasting state, 2 hr after breakfast or I hr before. The C , , , of both oxybutynin (P