Blood-brain barrier transport helps explain discrepancies in in vivo potency between oxycodone and morphine
Emma Boström, Margareta Hammarlund-Udenaes and Ulrika SH Simonsson
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24 Uppsala, Sweden
Objectives: The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic (PKPD) relationships of unbound oxycodone and morphine in order to investigate the influence of blood-brain barrier (BBB) transport on differences in potency between these drugs.
Methods: Microdialysis was used to obtain unbound concentrations in brain and blood. The antinociceptive effect of each drug was assessed using the hot water tail-flick method. A population PK model of morphine was developed using NONMEM. BBB transport was described as the rate (CLin) and extent (Kp,uu) of equilibration, where CLin is the influx clearance across the BBB and Kp,uu is the ratio of the unbound concentration in brain to that in blood at steady state. A joint PKPD model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the PD parameters of the drugs.
Results: A six-fold difference in Kp,uu between oxycodone and morphine implies that, for the same unbound concentration in blood, the concentrations of unbound oxycodone in brain will be six times higher than those of morphine. A direct effect model was applied to the unbound brain PKPD data. A power model using Effect = Baseline + Slope • Cγ best described the data. Drug-specific Slope and γ parameters were supported by the data, making the relative potency of the drugs concentration-dependent. Based on unbound brain concentrations, morphine was the more potent drug. However, based on unbound blood concentrations, oxycodone was more potent.
Conclusions: For centrally acting drugs such as opioids, PKPD relationships used for describing the interaction with the receptor are better obtained by correlating the effects to concentrations of unbound drug in the tissue of interest rather than to blood concentrations.