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Blood–Brain Barrier Transport Helps to Explain Discrepancies in In Vivo Potency between Oxycodone and Morphine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Farmakometri)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2008 (English)In: Anesthesiology, ISSN 0003-3022, E-ISSN 1528-1175, Vol. 108, no 3, 495-505 p.Article in journal (Refereed) Published
Abstract [en]

Background The objective of this study was to evaluate the brain pharmacokinetic-pharmacodynamic relations of un-bound oxycodone and morphine to investigate the influence of blood-brain barrier 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. Population pharmacokinetic modeling was used to describe the bloodbrain barrier transport of morphine as the rate (Cl.) and extent (K-p,K-uu) of equilibration, where CLin is the influx clearance across the blood-brain barrier and Kp,,,, is the ratio of the unbound concentration in brain to that in blood at steady state. Results: The six-fold difference in K-p,K-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 center dot C-gamma best described the data. Drug-specific slope and gamma parameters made the relative potency of the drugs concentration dependent. Conclusions: 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.

Place, publisher, year, edition, pages
2008. Vol. 108, no 3, 495-505 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95637DOI: 10.1097/ALN.0b013e318164cf9eISI: 000253395800021PubMedID: 18292687OAI: oai:DiVA.org:uu-95637DiVA: diva2:169934
Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport
Open this publication in new window or tab >>Pharmacokinetics and Pharmacodynamics of Oxycodone and Morphine with Emphasis on Blood-Brain Barrier Transport
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pharmacokinetics and pharmacodynamics of oxycodone and morphine was investigated and related to the transport across the blood-brain barrier (BBB) in rats. The influence of a P-glycoprotein (P-gp) inhibitor on the plasma pharmacokinetics and pharmacodynamics of oxycodone was evaluated. Microdialysis experiments were conducted to evaluate the unbound pharmacokinetics, including the rate and extent of transport across the BBB, of oxycodone and morphine. Mathematical models were used to assess the pharmacokinetics and also the relationship between pharmacokinetics and pharmacodynamics of the drugs.

Oxycodone clearance, volume of distribution at steady-state, half-life, total brain tissue concentrations and tail-flick latency were all unaffected when a P-gp inhibitor was co-administered with oxycodone as compared to a control group. The lack of differences between the groups indicates that oxycodone BBB transport is not affected by P-gp inhibition. Investigating the unbound concentrations of oxycodone in brain and blood using microdialysis revealed an exciting finding. At steady-state, the unbound concentration in brain was 3 times higher than in blood (i.e. a Kp,uu of 3), indicating that active influx is involved in the BBB transport of oxycodone. In contrast, the Kp,uu of morphine was estimated to 0.56, which is an indication that active efflux mechanisms are involved in the BBB transport of morphine. This means that based on the same unbound concentration in blood, an approximately 6-fold higher unbound concentration of oxycodone compared to morphine will be reached in the brain. Using pharmacokinetic-pharmacodynamic modelling, the unbound brain concentrations of oxycodone and morphine were correlated to the tail-flick latency in vivo. The relative potency of the drugs was found to be concentration dependent with an infliction point of 55 nM.

In summary, this thesis emphasise the importance of taking the local brain pharmacokinetics into consideration when investigating the pharmacokinetics and the pharmacokinetic-pharmacodynamic relationships of centrally acting drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 50
Keyword
Pharmacokinetics/Pharmacotherapy, pharmacokinetics, pharamcodynamics, blood-brain barrier, oxycodone, microdialysis, NONMEM, brain distribution, transport, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-7772 (URN)978-91-554-6840-8 (ISBN)
Public defence
2007-04-20, B22, Biomedical Centre (BMC), Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2007-03-30 Created: 2007-03-30Bibliographically approved

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Hammarlund-Udenaes, MargaretaSimonsson, Ulrika S. H.

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