PLASMA-CONCENTRATIONS OF MORPHINE, MORPHINE-3-GLUCURONIDE, AND MORPHINE-6-GLUCURONIDE AFTER INTRAVENOUS AND ORAL-ADMINISTRATION TO HEALTHY-VOLUNTEERS - RELATIONSHIP TO NONANALGESIC ACTIONS

Healthy volunteers were given morphine as an i.v. infusion (10 mg), im mediate release (IR) tablets (3 x 10 mg), and as a new controlled rele ase (CR) tablet (30 mg) on separate occasions. Venous blood samples we re analyzed for morphine, morphine-3-glucuronide (M3G), and morphine-6 -glucuronide (M6G) using high-performance liquid chromatography (HPLC) . Pupil size, salivation, and central nervous system (CNS) effects wer e evaluated serially. Pharmacokinetic parameters, calculated using a t wo-compartment model, were in accordance with previous results for i.v . administration of morphine. The absolute bioavailability of morphine in both IR and in CR tablets was, 32%, and the relative bioavailabili ty of the CR tablet versus the IR tablets was 103% (91-115%, 95% confi dence interval). Pupil size and unstimulated saliva production were si gnificantly reduced and CNS effects most pronounced following i.v. inf usion of morphine, but were only moderately affected after oral admini stration with IR or CR tablets. Miosis and reduction of salivation wer e observed at moderate concentrations of morphine and M6G. A pharmacok inetic/pharmacodynamic model based on previous studies of receptor bin ding and potency of morphine and its metabolites was used to assess th e concentration-effect relationships. According to this model, M6G was four and eight times more potent than morphine in producing miosis an d reduction of saliva production, respectively. The same model indicat ed that intrinsic activities of M6G and morphine were similar for both effect parameters, whereas M3G was either inactive or even opposed th e effects of morphine and M6G.