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Comparison of  blood-brain barrier transport of P-glycoprotein substrates in P-glycoprotein humanized, knock-out and wild type mice
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Translational PKPD Group)
(Translational PKPD Group)
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Pharmaceutical Science
URN: urn:nbn:se:uu:diva-180823OAI: oai:DiVA.org:uu-180823DiVA: diva2:551301
Available from: 2012-09-10 Created: 2012-09-10 Last updated: 2013-01-23
In thesis
1. In Vivo Active Drug Uptake and Efflux at the Blood-Brain Barrier: With Focus on Drug Transport Interactions
Open this publication in new window or tab >>In Vivo Active Drug Uptake and Efflux at the Blood-Brain Barrier: With Focus on Drug Transport Interactions
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The blood-brain barrier (BBB) controls the movement of substances into and out of the brain. The tight junctions between endothelial cells and energy dependent transporters in the BBB influence rate and extent of drug distribution to the brain.

The aim of this thesis was to study different methodological and pharmacokinetic aspects of drug transport at the BBB by characterizing possible active uptake and drug-drug interactions. Therefore, advanced tools for data acquisition and analysis were applied. The role of BBB transport in early drug development, with particular emphasis on in vitro-in vivo comparisons and species differences, was also investigated.

Microdialysis in rats was used to study the BBB pharmacokinetics of oxymorphone, diphenhydramine (DPHM), oxycodone and morphine. Oxymorphone, DPHM and verapamil were all found to be actively taken up at the BBB, with brain to blood unbound drug ratios of 2, 5 and 2, respectively. The effect profile for oxycodone was successfully described using the modified M3 method for censored observations. In vitro experiments indicated a competitive interaction between DPHM and oxycodone on active uptake transport to the brain. No such interaction was observed in vivo due to much lower unbound concentrations achieved, compared with the in vitro Ki values. Active uptake of morphine at the BBB was not demonstrated even at very low concentrations as it was not possible to separate the active uptake transport process from active efflux by decreasing the morphine concentration. Mice carrying the human P-gp gene (hMDR1) were used to evaluate possible species differences in P-gp function. Differences were evident between the hMDR1 and normal mice in BBB penetration of various P-gp substrates and in the effect of blockers on P-gp function. Quantitative measurements of P-gp expression levels at the BBB and a comparison with human data are crucial for the future use of the hMDR1 model.

In conclusion, this thesis reports active uptake of oxymorphone, DPHM and verapamil at the BBB. In vivo interaction of DPHM and oxycodone at the BBB was found not to be significant at therapeutic drug concentrations. Furthermore species differences were found between human and mouse P-gp function at the BBB.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 50 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 165
Blood-brain barrier, Active uptake transport, Microdialysis, P-glycoprotein, Drug interactions, Species differences, Pharmacokinetics, Pharmacodynamics, NONMEM
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
urn:nbn:se:uu:diva-180824 (URN)978-91-554-8472-9 (ISBN)
Public defence
2012-10-26, B:42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2012-10-04 Created: 2012-09-10 Last updated: 2013-01-23Bibliographically approved

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