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Research ArticleArticle

Morphine Brain Pharmacokinetics at Very Low Concentrations Studied with Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

Muhammad Waqas Sadiq, Mehran Salehpour, Niklas Forsgard, Göran Possnert and Margareta Hammarlund-Udenaes
Drug Metabolism and Disposition February 2011, 39 (2) 174-179; DOI: https://doi.org/10.1124/dmd.110.036434
Muhammad Waqas Sadiq
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Mehran Salehpour
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Niklas Forsgard
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Göran Possnert
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Margareta Hammarlund-Udenaes
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Abstract

Morphine has been predicted to show nonlinear blood-brain barrier transport at lower concentrations. In this study, we investigated the possibility of separating active influx of morphine from its efflux by using very low morphine concentrations and compared accelerator mass spectrometry (AMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a method for analyzing microdialysis samples. A 10-min bolus infusion of morphine, followed by a constant-rate infusion, was given to male rats (n = 6) to achieve high (250 ng/ml), medium (50 ng/ml), and low (10 ng/ml) steady-state plasma concentrations. An additional rat received infusions to achieve low (10 ng/ml), very low (2 ng/ml), and ultralow (0.4 ng/ml) concentrations. Unbound morphine concentrations from brain extracellular fluid and blood were sampled by microdialysis and analyzed by LC-MS/MS and AMS. The average partition coefficient for unbound drug (Kp,uu) values for the low and medium steady-state levels were 0.22 ± 0.08 and 0.21 ± 0.05, respectively, when measured by AMS [not significant (NS); p = 0.5]. For the medium and high steady-state levels, Kp,uu values were 0.24 ± 0.05 and 0.26 ± 0.05, respectively, when measured by LC-MS/MS (NS; p = 0.2). For the low, very low, and ultralow steady-state levels, Kp,uu values were 0.16 ± 0.01, 0.16 ± 0.02, and 0.18 ± 0.03, respectively, when measured by AMS. The medium-concentration Kp,uu values were, on average, 16% lower when measured by AMS than by LC-MS/MS. There were no significant changes in Kp,uu over a 625-fold concentration range (0.4–250 ng/ml). It was not possible to separate active uptake transport from active efflux using these low concentrations. The two analytical methods provided indistinguishable results for plasma concentrations but differed by up to 38% for microdialysis samples; however, this difference did not affect our conclusions.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.036434.

  • ABBREVIATIONS:

    CNS
    central nervous system
    BBB
    blood-brain barrier
    ISF
    interstitial fluid
    Kp,uu
    partition coefficient for unbound drug
    Pgp
    P-glycoprotein
    GF120918
    N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
    AMS
    accelerator mass spectrometry
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    ACN
    acetonitrile
    TFA
    trifluoroacetic acid
    D3
    deuterated
    LC
    liquid chromatography
    Vblood
    volume of blood per g brain.

  • Received September 22, 2010.
  • Accepted November 8, 2010.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (2)
Drug Metabolism and Disposition
Vol. 39, Issue 2
1 Feb 2011
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Research ArticleArticle

Morphine Brain Pharmacokinetics at Very Low Concentrations Studied with Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

Muhammad Waqas Sadiq, Mehran Salehpour, Niklas Forsgard, Göran Possnert and Margareta Hammarlund-Udenaes
Drug Metabolism and Disposition February 1, 2011, 39 (2) 174-179; DOI: https://doi.org/10.1124/dmd.110.036434

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Research ArticleArticle

Morphine Brain Pharmacokinetics at Very Low Concentrations Studied with Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

Muhammad Waqas Sadiq, Mehran Salehpour, Niklas Forsgard, Göran Possnert and Margareta Hammarlund-Udenaes
Drug Metabolism and Disposition February 1, 2011, 39 (2) 174-179; DOI: https://doi.org/10.1124/dmd.110.036434
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