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Oxycodone Pharmacokinetics and Pharmacodynamics in the Rat in the Presence of the P-Glycoprotein Inhibitor PSC833
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.
2005 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 94, no 5, 1060-1066 p.Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to investigate the in vivo influence of the P-glycoprotein (P-gp) inhibitor PSC833 on the plasma pharmacokinetics, total brain concentrations and tail-flick latency of oxycodone in rats. Eight rats each received an infusion of PSC833 or vehicle without PSC833. One hour later, all animals received 0.3 mg/kg oxycodone as a 1-h infusion. Plasma samples were taken, and tail-flick latency was monitored during the infusion and for 2 h thereafter. The brains were collected at the end of the experiment. There were no differences between the two groups in area under the plasma oxycodone concentration-time curve from time zero to infinity, or oxycodone plasma clearance, volume of distribution at steady-state, or half-life. There were no differences in average total brain oxycodone concentrations at 180 min, nor were there any differences in average tail-flick latency for the PSC833 and control groups. In conclusion, coadministration of PSC833 did not alter the plasma pharmacokinetics, brain concentrations, or associated tail-flick latency of oxycodone, indicating that oxycodone is not a P-gp substrate in the rat. This has important clinical implications, as it indicates that oxycodone, unlike some other opioids, will not interact at the blood-brain barrier (BBB) with concomitantly administered P-gp substrates.

Place, publisher, year, edition, pages
2005. Vol. 94, no 5, 1060-1066 p.
Keyword [en]
P-glycoprotein, pharmacokineties/pharmacodynamics, blood-brain barrier, efflux pumps, active transports, transporters, CNS, clearance
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95635DOI: 10.1002/jps.20327ISI: 000228792200014PubMedID: 15799017OAI: oai:DiVA.org:uu-95635DiVA: diva2:169932
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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Simonsson, Ulrika S. H.Hammarlund-Udenaes, Margareta

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