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Diphenhydramine Active Uptake at the Blood-Brain Barrier and Its Interaction with Oxycodone in Vitro and in Vivo
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
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2011 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, 3912-3923 p.Article in journal (Refereed) Published
Abstract [en]

Diphenhydramine (DPHM) and oxycodone are weak bases that are able to form cations. Both drugs show active uptake at the blood-brain barrier (BBB). There is thus a possibility for a pharmacokinetic interaction between them by competition for the same uptake transport system. The experiments of the present study were designed to study the transport of DPHM across the BBB and its interaction with oxycodone in vitro and in vivo. In vitro, the interaction between the drugs was studied using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13 cells). The in vivo relevance of the in vitro findings was studied in rats using brain and blood microdialysis. DPHM was actively transported across the BBB in vitro (TR-BBB13 cells). Oxycodone competitively inhibited DPHM uptake with a K(i) value of 106 mu M. DPHM also competitively inhibited oxycodone uptake with a K(i) value of 34.7 mu M. In rats, DPHM showed fivefold higher unbound concentration in brain interstitial fluid (ISF) than in blood, confirming a net active uptake. There was no significant interaction between DPHM and oxycodone in vivo. This accords with the results of the in vitro experiments because the unbound plasma concentrations that could be attained in vivo, without causing adverse effects, were far below the Ki values.

Place, publisher, year, edition, pages
2011. Vol. 100, no 9, 3912-3923 p.
Keyword [en]
blood-brain barrier, drug interactions, organic cation transporters (OCTs), pharmacokinetics, active transport, HPLC (high-performance/pressure liquid chromatography), mass spectrometry
National Category
Medical and Health Sciences Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-159250DOI: 10.1002/jps.22567ISI: 000294666600030OAI: oai:DiVA.org:uu-159250DiVA: diva2:443641
Available from: 2011-09-26 Created: 2011-09-26 Last updated: 2013-02-01Bibliographically approved
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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