PHARMACOKINETIC-PHARMACODYNAMIC MODELING OF THE ELECTROENCEPHALOGRAM EFFECT OF SYNTHETIC OPIOIDS IN THE RAT - CORRELATION WITH THE INTERACTION AT THE MU-OPIOID RECEPTOR

The purpose of our investigation was to characterize the relationships between the pharmacodynamics of synthetic opioids in vivo and the int eraction at the mu-opioid receptor. The pharmacokinetics and pharmacod ynamics were determined in vivo after a single i.v. infusion of 3.14 m g/kg alfentanil (A), 0.15 mg/kg fentanyl (F) or 0.030 mg/kg sufentanil (S) in rats. Amplitudes in the 0.5 to 4.5 Hz frequency band of the el ectroencephalogram (EEG) was used as pharmacodynamic endpoint. The EEG effect intensity was related to the (free) concentration in blood (A) or in a hypothetical effect compartment (F, S) on basis of the sigmoi dal E-max pharmacodynamic model. The interaction at the mu-opioid rece ptor was determined in vitro on basis of the displacement of [H-3]-nal oxone binding in washed rat brain membranes. The value of the sodium s hift was used as a measure of in vitro intrinsic efficacy. For the EEG effect the in vivo potencies based on free drug concentrations (EC50, u) were 4.62 +/- 0.66 ng/ml (A), 0.69 +/-: 0.05 ng/ml (F) and 0.29 +/- 0.06 ng/ml (S). In the receptor binding studies the affinities at the mu-opioid receptor (K-1) were 47.4 +/- 6.6 nM (A), 8.6 +/- 4.1 nM (F) and 2.8 +/- 0.2 nM (S). For each opioid the ratio between EC50,u and K-1 was the same with a value of 0.23-0.25, indicating the existence o f receptor reserve for the EEG effect. The intrinsic activity (E-max) of the three opioids in vivo was similar with values of 111 +/- 10 mu V (A), 89 +/- 11 mu V (F) and 104 +/- 4 mu V (S). However, the values of the sodium shift varied between 2.8 (S) and 19.1 (A). Further analy sis of the in vivo pharmacodynamic data on basis of an operational mod el of agonism provided evidence for a large receptor reserve, which ex plains why compounds with different values of the sodium shift all beh ave as full agonists in vivo.