The comparative pharmacodynamics of remifentanil and its metabolite, GR90291, in a rat electroencephalographic model

Background The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. Methods: Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. Results: Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 mu g/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920 +/- 110 ml . min(-1). kg(-1) and 1.00 +/- 0.93 l/kg for remifentanil and 15 +/- 2 ml.min(-1).kg(-1) and 0.56 +/- 0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25 +/- 5% and 0.30 +/- 0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal E-max pharmacodynamic model The mean +/- SE values for the maximal effect (E-max), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109 +/- 12 mu V, 9.4 +/- 0.9 ng/ml, and 2.2 +/- 0.3, respectively (n = 8), For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000 +/- 9,000 mu g/ml and 2.5 +/- 0.4, respectively (n = 6). Conclusions: Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the CL-opioid receptor in combination with a poor brain penetration.