Marie Gårdmark, Mats O Karlsson and Margareta Hammarlund-Udenaes
Division of Biopharmaceutics and Pharmacokinetics, Uppsala University,
This investigation was carried out to evaluate if and to what extent morphine-3-glucuronide (M3G) antagonise morphine antinociceptive effects or is involved in the development of acute tolerance. The rats received M HCl as an infusion for 3 hours, 10mg/h/kg (A) (n=22) or 20mg/h/kg (B) (n=21). Both groups were pretreated with saline infusion (I), M3G-infusion (4.3mg/h/kg) (II) or M3G-infusion (17.4mg/h/kg) (III). As the morphine infusion started the M3G infusion was stepwise decreased to correct for the formed M3G. The experimental design included measurement of the antinociceptive effect (electrical stimulation vocalisation) and of respiratory parameters (pCO2, pO2, pH). Plasma samples were analysed for M and M3G.
For the groups A and B, respectively, the antinociceptive effect increased concurrently during the first hour irrespective of M3G-pretreatment. However, the maximal antinociceptive effect were lower in rats pretreated with the high M3G-infusion (III). Acute tolerance was observed in all groups.
The concentrations of M and M3G were described nonparametrically by linear interpolation. Several PD-models were tested. We chose a model that explained the acute toleration, the concurrent upswing and the diversity in maximal effect depending on M3G pretreatment. The model includes two additive effects to describe the overall antinociceptive effect. Effect 1 is directly related to the morphine concentration by a linear relationship characterised by the slope S1. To explain the acute tolerance, Effect 1 was modified by the formation of a hypothetical non-competitive antagonist. The îantagonist” exposure was assumed to be proportional to morphine AUC up to time t, which suggests that the extent of tolerance is a result of the cumulative exposure of morphine. AUC50 quantifies the degree of tolerance. Effect 2 is delayed and is described by an effect compartment linked to the plasma compartment. The equilibration time is estimated by ke0. The effect is linearly related to the concentration in the effect compartment with the slope S2. M3G antagonise the delayed effect, by decreasing the sensitively of the effect (S2).
The equilibrium half-life for the delayed effect was 42 min. The M3G concentrations needed to decrease S2 by one-half was 29.5µM (95% CI: 13-91µM). The slopes S1 and S2 were 0.64 (12%) and 0.42 (29%) V/µM, respectively. This implies that at steady state following a morphine infusion (AI) of 20mg/h/kg (M=14µM, M3G=20µM), M3G decreases the antinociceptive effect by 20%. The model estimated AUC50 to 11.2µM*h (23%). The rats varied in AUC50 (inter-individual variability of 88%) which was not explained by different M3G-pretreatments.
In conclusion, this model managed well to quantify the interaction between morphine and its metabolite M3G and the acute tolerance development.
Reference: PAGE 5 (1996) Abstr 575 [www.page-meeting.org/?abstract=575]
Poster: poster