Characterization of the antinociceptive effects of morphine and its glucuronides : Pharmacokinetic-pharmacodynamic modeling

Abstract: Pharmacodynamic modeling was used to quantify the time aspects of theantinociceptive effect in rats following administration of morphine, morphine-3-glucuronide (M3G) and morphine-glucuronide (M6G). M6G acts as a potentagonist of morphine actions, whereas the pharmacodynamic role of M3G has beenunclear. The nociceptive effect was measured as the response to electrical stimulation to the tail and the respiratory effect was obtained by measuring the blood gas status. The electrical stimulation vocalization method was shown to be a suitable method for measuring morphine antinociception. Pharmacodynamic models were applied to the data and parameters describing the concentration-effect relationship were estimated.The data analysis was performed in NONMEM and PCNONLIN.The antinociceptive effect of M6G developed slowly with an equilibrationhalf-life of 1.4 h. This is considerably longer than the half-life of 0.5 h estimated for morphine. Acute tolerance was observed following morphine administration and developed with a half-life of 0.8 h. Following M6G administration acute tolerance was observed, but could not be described by the pharmacodynamic model applied. M3G was demonstrated to have a minor antagonistic influence on morphine antinociception. Based on behavioral observations and literature data, the interaction was hypothesized to be caused by the behavioral effects of M3G.The interchangeability and predictive performance of empirical tolerancemodels, some of which are used in this thesis, were evaluated. There was a large degree of interchangeability among the models. The predictive capability of a model was linked to the original study design, whereas the correlation between type of model and predictive performance was weak or absent. For the model selecting process it is suggested that several models