Pharmacokinetic/pharmacodynamic modelling of the EEG effects of opioids: the role of complex biophase distribution kinetics.

Abstract The objective of this investigation is to characterize the role of complex biophase distribution kinetics in the pharmacokinetic–pharmacodynamic correlation of a wide range of opioids. Following intravenous infusion of morphine, alfentanil, fentanyl, sufentanil, butorphanol and nalbuphine the time course of the EEG effect was determined in conjunction with blood concentrations. Different biophase distribution models were tested for their ability to describe hysteresis between blood concentration and effect. In addition, membrane transport characteristics of the opioids were investigated in vitro , using MDCK:MDR1 cells and in silico with QSAR analysis. For morphine, hysteresis was best described by an extended-catenary biophase distribution model with different values for k 1e and k eo of 0.038 ± 0.003 and 0.043 ± 0.003 min −1 , respectively. For the other opioids hysteresis was best described by a one-compartment biophase distribution model with identical values for k 1e and k eo . Between the different opioids, the values of k 1e ranged from 0.04 to 0.47 min −1 . The correlation between concentration and EEG effect was successfully described by the sigmoidal E max pharmacodynamic model. Between opioids significant differences in potency (EC 50 range 1.2–451 ng/ml) and intrinsic activity ( α range 18–109 μV) were observed. A statistically significant correlation was observed between the values of the in vivo k 1e and the apparent passive permeability as determined in vitro in MDCK:MDR1 monolayers. It can be concluded that unlike other opioids, only morphine displays complex biophase distribution kinetics, which can be explained by its relatively low passive permeability and the interaction with active transporters at the blood–brain barrier.