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The use of a deuterated calibrator for in vivo recovery estimations in microdialysis studies
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.
2008 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, no 8, 3433-3441 p.Article in journal (Refereed) Published
Abstract [en]

One of the crucial issues in quantitative microdialysis is the reliability of recovery estimates to correctly estimate unbound drug tissue concentrations. If a deuterated calibrator is used for retrodialysis, the calibrator has the same properties as the study drug. However, recovery of the calibrator may be affected by the presence of the drug in the tissues. The aim of this study was to investigate the recovery of deuterated morphine with time in the absence and presence of morphine in rat tissues. Microdialysis probes were placed in the brain and blood of eight rats. Ringer's solution containing D3-morphine was perfused throughout the study and recovery was estimated. After a stabilization period of 3 h, an exponential infusion of morphine was administered over 4 h. The presence of morphine did not affect the recovery of D3-morphine from brain or blood. The average recovery values (SD) were 0.145 (0.039) and 0.131 (0.048) during the stabilization and infusion periods, respectively, for the brain probe and 0.792 (0.055) and 0.790 (0.084), respectively, for the blood probe. The recovery of deuterated morphine was stable over time in the brain and in blood, and was not affected by the presence of pharmacologically concentrations of morphine.

Place, publisher, year, edition, pages
2008. Vol. 97, no 8, 3433-3441 p.
Keyword [en]
microdialysis, active transport, blood-brain barrier, efflux pumps, ABC transporters
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13336DOI: 10.1002/jps.21217ISI: 000258081100042PubMedID: 17990306OAI: oai:DiVA.org:uu-13336DiVA: diva2:41106
Available from: 2008-01-22 Created: 2008-01-22 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Developmental Aspects of Drug Transport Across the Blood-Brain Barrier
Open this publication in new window or tab >>Developmental Aspects of Drug Transport Across the Blood-Brain Barrier
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The developmental aspect of drug transport across the blood-brain barrier (BBB) was investigated. Microdialysis was used to study unbound morphine BBB transport at different ages in sheep. An in vitro study was performed to find differentially expressed genes in brain capillary-rich fractions of the brain in rats of different ages. Microdialysis and brain-to-plasma ratios were used to study the contribution of breast cancer resistance protein (Bcrp) to the transport of nitrofurantoin (NTF) across the BBB of rats during development as well as in adult rats and mice.

A method of analysing morphine and its metabolites in plasma and microdialysis samples was developed and validated. The in vivo recovery of deuterated morphine, used as a calibrator in microdialysis experiments, was not affected by the presence of morphine in the tissue. A net influx of morphine was observed in premature lambs and adult sheep, in contrast to the efflux seen in other species. This influx decreased with age, indicating that the morphine transport across the BBB changes with age. In contrast, the transport of the morphine metabolite morphine-3-glucuronide (M3G) did not change with age. Microarray data indicated that several active transporters are differentially expressed with age. Moreover, the mRNA expression levels of Abcg2 (Bcrp) and Slc22a8 (organic anion transporter 3) changed with age when quantified using real-time polymerase chain reaction. In contrast, the expression of Abcb1 (P-glycoprotein) and occludin (a tight junction protein) did not change with age. In rats, the brain distribution of NTF decreased with age due to increased protein binding in plasma. The concentration ratio of unbound NTF across the BBB was low in the adult rat, due to intra-brain metabolism and/or efflux by other transporters. Bcrp did not appear to have a significant contribution in the developing rat or in knock-out mice compared to wild-type controls with regard to NTF BBB transport.

In conclusion, in vitro studies showed that the expression levels of some genes changed with age, presumably affecting subsequent drug distribution to the brain. Further, in vivo studies showed that distribution across the BBB changed with age for morphine but not for M3G or NTF.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 60 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 110
Keyword
Blood-brain barrier, development, active transport, tight junction proteins, microdialysis, recovery, morphine, nitrofurantoin, Bcrp, microarray, real-time PCR, in vitro, in vivo, LC-MS/MS
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-108374 (URN)978-91-554-7627-4 (ISBN)
Public defence
2009-11-26, B42, Biomedicinskt Centrum, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-11-04 Created: 2009-09-17 Last updated: 2011-05-11Bibliographically approved

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Bengtsson, JörgenHammarlund-Udenaes, Margareta

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