Morphine brain pharmacokinetics at very low concentrations studied with Accelerator Mass Spectrometry and Liquid Chromatography-tandem Mass Spectrometry
2011 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 39, no 2, 174-179 p.Article in journal (Refereed) Published
Morphine has been predicted to show nonlinear blood-brain barrier (BBB) transport at lower concentrations. Present study investigated the possibility of separating active influx of morphine from its efflux by using very low morphine concentrations, and to compare AMS with LC-MS/MS as method for analysing 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(-1)), medium (50 ng.ml(-1)) and low (10 ng.ml(-1)) steady-state plasma concentrations (C(ss)). An additional rat received infusions to achieve low (10 ng.ml(-1)), very low (2 ng.ml(-1)) and ultra low (0.4 ng.ml(-1)) concentrations. Unbound morphine concentrations from brain extracellular fluid and blood were sampled with microdialysis and analysed by LC-MS/MS and AMS. The average K(p,uu) for the low and medium steady-state levels were 0.22±0.08 and 0.21±0.05, when measured with AMS (NS; p=0.5). For the medium and high steady-state levels, K(p,uu) values were 0.24±0.05 and 0.26±0.05, measured with LC-MS/MS (NS; p=0.2). For the low, very low and ultra low levels, K(p,uu) values were 0.16±0.01, 0.16±0.02 and 0.18±0.03, respectively, measured with AMS. The medium-concentration K(p,uu) values were, on average, 16% lower with AMS than with LC-MS/MS. There were no significant changes in K(p,uu) over a 625-fold concentration range (0.4-250 ng.ml(-1)). It was not possible to separate active uptake transport from active efflux using these low concentrations. The two analytical methods provided indistinguishable results for blood plasma concentrations, but differed by up to 38% for microdialysis samples; however, this did not affect our conclusions.
Place, publisher, year, edition, pages
2011. Vol. 39, no 2, 174-179 p.
Research subject Pharmacokinetics and Drug Therapy
IdentifiersURN: urn:nbn:se:uu:diva-141822DOI: 10.1124/dmd.110.036434ISI: 000286317900004PubMedID: 21059857OAI: oai:DiVA.org:uu-141822DiVA: diva2:386276