Pharmacokinetic/pharmacodynamic modelling of the EEG effects of opioids: the role of complex biophase distribution kinetics.
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 k1e and keo 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 k1e and keo. Between the different opioids, the values of k1e ranged from 0.04 to 0.47 min(-1). The correlation between concentration and EEG effect was successfully described by the sigmoidal Emax pharmacodynamic model. Between opioids significant differences in potency (EC50 range 1.2-451 ng/ml) and intrinsic activity (alpha range 18-109 microV) were observed. A statistically significant correlation was observed between the values of the in vivo k1e 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.
Groenendaal
Dorien
D
Leiden Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, PO Box 9502, 2300 RA Leiden, The Netherlands.
Freijer
Jan
J
Rosier
Andrea
A
de Mik
Dennis
D
Nicholls
Glynis
G
Hersey
Anne
A
Ayrton
Andrew D
AD
Danhof
Meindert
M
de Lange
Elizabeth C M
EC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000465:Algorithms; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004058:Diffusion; D004285:Dogs; D004569:Electroencephalography / Q000187:drug effects*; D008297:Male; D015233:Models, Statistical; D010539:Permeability; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid