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BOSTRÖM, Emma; HAMMARLUND-UDENAES, Margareta; SIMONSSON, Ulrika S. H
Anesthesiology (Philadelphia) 108, Številka: 3Journal Article
The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of unbound oxycodone and morphine to investigate the influence of blood-brain barrier transport on differences in potency between these drugs. 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. Population pharmacokinetic modeling was used to describe the blood-brain barrier transport of morphine as the rate (CLin) and extent (Kp,uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,uu is the ratio of the unbound concentration in brain to that in blood at steady state. The 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 joint pharmacokinetic-pharmacodynamic model of oxycodone and morphine based on unbound brain concentrations was developed and used as a statistical tool to evaluate differences in the pharmacodynamic parameters of the drugs. A power model using Effect = Baseline + Slope . C best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. For centrally acting drugs such as opioids, pharmacokinetic-pharmacodynamic relations 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.
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