In this study the pharmacokinetics and pharmacodynamics of morphine-3-glucuronide (M3G) were investigated in rats after i.v. administration as a bolus dose (86.7 mumol kg-1) and as a constant rate infusion (2.9 mumol h-1) over 5 days. After the bolus dose, the clearance (Cl) was 12.1 +/- 0.6 ml min-1*kg, the volume of distribution at steady state (Vss) 1.68 +/- 0.89 l kg-1, the half-life of the first phase 13.2 +/- 1.8 min and the half-life of the second phase 11.6 +/- 7.7 h. After the constant rate infusion, Cl was 10.5 +/- 1.7 ml min-1*kg. The antagonistic effect of M3G on the antinociceptive effect of a bolus dose of morphine (35 mumol kg-1) was tested during steady state concentrations of M3G on day 4 and to M3G naïve rats. No antinociceptive, hyperalgesic or withdrawal effects were observed as a result of M3G administration, but a significantly lower antinociceptive effect of morphine was found in the M3G infusion group compared to the control group. Systemically administered M3G antagonized the antinociceptive effect of morphine, but this cannot be the only explanation to the tolerance development observed after morphine administration.
Abstract:The objective of this study was to compare the results of three nociceptive tests, tail-flick, hot-plate and electrical stimulation vocalisation, reflecting the responses from different sites in the CNS. A subcutaneous morphine dose (5 mgl kg) was administered to three parallel groups of rats in which the nociceptive response was measured by one of the three methods. The baseline decreased during the period of measurement for the hot-plate test, but remained stable for the other methods. The spinally mediated tail-flick response was more sensitive to the morphine effects as compared to the supraspinally mediated hot-plate and electrical stimulation vocalisation responses. The electrical stimulation vocalisationtest demonstrated more even effect-time profiles and less variability among the rats than did the tail-flick and the hotplate methods. In the tail-flick group, 59% of the observations attained the cut-off latency at this morphine dose, leading to underestimation of the peak effect, the area under the effect curve (AUEC), and the variability among the rats. In the hot-plate group, 13% of the observations were at the cut-off latency, and 2% in the electrical stimulation vocalisation group. Different ways of presenting the data are discussed. In conclusion, the test selected for measuring the nociceptive response will influence the effect-time profile and subsequently any pharmacodynamic parameters describing it.
Models of tolerance are commonly derived on empirical grounds, because of lack of knowledge about the mechanism of tolerance or because of the difficulty of appropriately simplifying complex physiological processes. The present study was performed to evaluate the interchangeability of tolerance models used in the literature and to address some determinants for selection of an appropriate design and data analysis strategy. Seven models were chosen (noncompetitive antagonist model, partial agonist model, reverse agonist model, direct moderator model, indirect moderator model, pool model and adaptive pool model) along with their corresponding parameter estimates, representing a wide range of empirical models. The performance of the models on various data sets was evaluated. Data were simulated from each original model and were further analysed by the other models. The effect-time course of each and every data set could be described well by at least 2 different empirical tolerance models, but no model could describe all the data sets adequately. However, all models could adequately describe at least 2 different data sets. This indicates that, without additional knowledge or assumptions, it is unlikely that reliable mechanistic information can be deduced from the mere fact that 1 (or more) of these models can describe the data. Generally, data expressing only limited tolerance can be described by a wide variety of models, whereas few models will be appropriate for data characterised by extensive tolerance. The models that gave an adequate description of a data set were selected for further study that investigated their predictive capacity based on the parameters previously determined. Predictions were made for 4 different administration schemes. The selected models gave similar predictions for the extended designs of 3 data sets for which the original study designs characterised tolerance well. For the other 4 data sets, the selected models gave disparate predictions, although the models described the original data set well. Thus, the predictive capability of a model was linked to the original study design, whereas the correlation between predictive performance and the type of model was weak or absent. Based on the results, factors of importance for the design and evaluation of studies of tolerance were identified and discussed.
The objective of this study was to quantify the influence of morphine-3-glucuronide (M3G) on the morphine antinociceptive effect (ANE) and respiratory effects in the rat. Three groups of rats were pretreated with either saline or M3G at two different rates. Morphine infusion of 10 mg/h/kg (group A) or 20 mg/h/kg (group B) was administered to each pretreatment group for 3 h. The ANE was measured by the electrical stimulation vocalization method, and blood gas parameters (pCO2, pO2, and pH) were assessed. Independent of pretreatment all groups displayed a concurrent increase in the ANE. The maximal effect diverged between pretreatments. Acute tolerance was observed, but no rebound effect was detected. To characterize the ANE, an effect compartment model and an indirect response model were selected, both capable of describing the observed features. In both models incorporation of M3G led to a better explanation of the data. On the basis of the parameters obtained in the fits, naturally occurring M3G would reduce the antinociceptive effect during a morphine infusion (plasma concentration 15 microM) by 15-20%. The exposure of M3G did not significantly change the respiratory response following the morphine treatment.
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.
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