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The Use of Liquid Chromatography/Mass Spectrometry for Quantitative Analysis of Oxycodone, Oxymorphone and Noroxycodone in Ringer Solution, Rat Plasma and Rat Brain Tissue
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
2004 (English)In: Rapid Communications in Mass Spectrometry, ISSN 0951-4198, E-ISSN 1097-0231, Vol. 18, no 21, 2565-2576 p.Article in journal (Refereed) Published
Abstract [en]

Sensitive and reproducible methods for the determination of oxycodone, oxymorphone and noroxycodone in Ringer solution, rat plasma and rat brain tissue by liquid chromatography/mass spectrometry are described. Deuterated analogs of the substances were used as internal standards. Samples in Ringer solution were analyzed by direct injection of 10 microL Ringer solution diluted by an equal volume of water. The limit of quantification was 0.5 ng/mL and the method was linear in the range of 0.5-150 ng/mL for all substances. To analyze oxycodone and oxymorphone in rat plasma, 50 microL of plasma were precipitated with acetonitrile, and the supernatant was directly injected onto the column. To analyze oxycodone, oxymorphone and noroxycodone in rat plasma, 100 microL of rat plasma were subjected to a C18 solid-phase extraction (SPE) procedure, before reconstituting in mobile phase and injection onto the column. For both methods the limit of quantification in rat plasma was 0.5 ng/mL and the methods were linear in the range of 0.5-250 ng/mL for all substances. To analyze the content of oxycodone, oxymorphone and noroxycodone in rat brain tissue, 100 microL of the brain homogenate supernatant were subjected to a C18 SPE procedure. The limit of quantification of oxycodone was 20 ng/g brain, and for oxymorphone and noroxycodone 4 ng/g brain, and the method was linear in the range of 20-1000 ng/g brain for oxycodone and 4-1000 ng/g brain for oxymorphone and noroxycodone. All methods utilized a mobile phase of 5 mM ammonium acetate in 45% acetonitrile, and a SB-CN column was used for separation. The total run time of all methods was 9 min. The intra-day precision and accuracy were <11.3% and <+/-14.9%, respectively, and the inter-day precision and accuracy were <14.9% and <+/-6.5%, respectively, for all the concentrations and matrices described.

Place, publisher, year, edition, pages
2004. Vol. 18, no 21, 2565-2576 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95634DOI: 10.1002/rcm.1658ISI: 000224872500007PubMedID: 15468158OAI: oai:DiVA.org:uu-95634DiVA: diva2:169931
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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Jansson, BrittHammarlund-Udenaes, MargaretaSimonsson, Ulrika S. H.

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