Ten healthy volunteers were given an i.v. infusion of 10 mg morphine HCl, an oral solution of 20 mg morphine HCl, or a new controlled release tablet of 30 mg morphine sulphate on three separate occasions in a complete crossover design. Venous blood samples were collected serially for 14-24 h and analyzed for morphine using high-performance liquid chromatography (HPLC). Continuous reaction times (CRTs) and salivation were measured repeatedly in all subjects. Oxygen saturation remained normal throughout the procedure. Five subjects experienced nausea on at least one occasion. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. and oral administration of morphine solutions. The absolute bioavailability of morphine in the oral solution was 21.6% (15.4-27.7%; 95% CI) and in the controlled release tablet, 17.1% (12.6-21.6%; CI). Secondary peaks in the plasma concentration curves strongly indicated an enterohepatic circulation (EHC) of morphine. Alternative pharmacokinetic calculations, including EHC, were performed and used in a pharmacokinetic-pharmacodynamic model, in which the studied effects were well correlated to the concentrations of morphine.
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