Delayed antinociceptive effect following morphine-6-glucuronide administration in the rat – pharmacokinetic/pharmacodynamic modelling

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Abstract
This study was conducted with the aim of characterising the pharmacokinetics and pharmacodynamics of morphine-6-glucuronide (M6G), a morphine metabolite possessing agonist properties. M6G was administered to three groups of rats as either a bolus dose, a 2-h computer-controlled stepwise infusion or as two consecutive 30-min infusions given 3 h apart. Clearance and initial volume of distribution were estimated to be 27 ml/min/kg for clearance and 339 ml/kg for initial volume. Morphine could not be detected until 4 h after dosing. The antinociceptive response profile, measured using the electrical stimulation vocalisation method, showed a pronounced delay in relation to the plasma concentration profile. The peak concentrations of 12 000 ng/ml, 6270 ng/ml and 12 800 ng/ml in the bolus, the stepwise infusion and the two consecutive infusion groups gave corresponding maximal antinociceptive effects of 49%, 181% and 168%. A pharmacokinetic-pharmacodynamic model was applied to the data and the effect delay was estimated to be 1.4 h, which is considerably longer compared to morphine (0.5 h). Acute tolerance to the antinociceptive response was observed but could not be quantified due to the slowly ascending effect. Based on these results, the importance of study design for potency determination of drugs exhibiting different effect equilibration times was elucidated. Significant increases in the pCO2 levels were observed following the stepwise infusion and the two consecutive infusions. When compared to morphine, there was a tendency of a less pronounced effect on respiration by M6G.