We have studied the effect of propofol on the enzymatic degradation of alfentanil and sufentanil utilizing isolated liver microsomes obtained from pig and human liver. Propofol inhibited dose-dependently the oxidative metabolic degradation of alfentanil and sufentanil by both microsomal preparations. The calculated concentration of propofol causing 50% inhibition of metabolic degradation (IC50) was 32.6 mumol litre-1 for alfentanil and 22.1 mumol litre-1 for sufentanil in pig liver microsomes. Similar values of inhibitory activity of propofol (IC50 values 62.8 and 52.9 mumol litre-1, respectively) were observed using human microsomes prepared from liver taken from an organ transplant donor. We suggest that propofol in clinically relevant concentrations interferes with oxidative metabolic degradation of alfentanil and sufentanil in the microsomal fraction of pig and human liver.
The recent series of papers about morphine-pharmacokinetics has revealed that active morphine (M) metabolite -morphine-6-glucuronide (M6G) -might play an important role in the analgesic response to M (Osborne et al. 1990;Peterson et al. 1990; Poulain el al. 1990). We felt that this active metabolite may also be involved in differential tolerance development to various peripheral effects of M observed during prolonged M treatment and, what is probably more important from the clinical point of view, that the relative ratio of M6G to M may be different after various methods of treatment in humans (Peterson et al. 1990).The study protocol was accepted by the Ethics and Research Committee of the University of Cape Town. Our experiments were performed on male rats weighing 300-320 g. We compared the gastric emptying (as measured by paracetamol absorption, Petring & Flachs 1990) in four groups of rats: ( I ) a control, rats which received no M; (2) naive rats given a single dose of 5 mg/kg M subcutaneously, 20 min before paracetamol administration; (3) rats treated for 6 days with oral M (M dissolved in drinking water in the gradually increasing concentrations from 0.2 to 0.4 mg/mL); (4) rats implanted subcutaneously with M slow release pellets (total M dose was 90 mg for 5 days). All experiments were performed under halothane (1.5% v/v) anaesthesia. Paracetamol(36 mg/kg) was administered intragastrically. Blood samples (0.5 mL) were taken via femoral vein catheter for HPLC analysis of paracetamol concentration from 1 to 120 min after its administration. The extent of paracetamol absorption was measured as Cmax, T m a x and total plasma area under the curve (AUC) and compared between various experimental groups (one-way ANOVA, followed by Student's t-test).The blood and brain samples taken at the end of the experiment were analysed for M and M6G using a specific HPLC assay method (Svensson et al. 1982): there was no statistically significant difference between the oral and parenteral groups in respect to the plasma (632 vs 712 ng/mL, respectively) and brain concentration of M (178 vs 204 ng/g, respectively). An attempt was made to correlate measurement of gastric emptying with the M6G: M concentration ratio observed in plasma and brain tissue. Our previous experiments have shown that the administration of sucrose solution or implantation of placebo tablets did not influence gastric emptying as measured by the paracetamol method when compared with non-treated animals. The results of gastric emptying are shown in Table 1. The single-dose of acutely administered M caused a significant delay of gastric emptying as revealed by both decrease in Cmax and total AUC for paracetamol as well as increase of its Tmax. The pharmacokinetic parameters of paracetamol (and, thus, gastric emptying) in rats implanted with slowrelease M tablets did not differ significantly from control animals in respect of all measured parameters (i.e. Cmax, T,,, and AUC) indicating that tolerance
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