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Bcrp does not influence transport of nitrofurantoin across the blood-brain barrier at different ages
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy. (Margareta Hammarlund-Udenaes)
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan..
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In the blood-brain barrier (BBB), tight junction proteins together with active efflux transporters efficiently restrict access of many compounds to the brain. The contribution of breast cancer resistance protein (Bcrp, coded by Abcg2) for drug efflux in the BBB is not clear. The aim of this study was to investigate the contribution of Bcrp in the rat BBB and how development affects distribution of a Bcrp substrate with age. Nitrofurantoin (NTF) is a good substrate for Bcrp and was used as model substance. Brain-to-plasma concentration ratio (Kp) of NTF was measured at postnatal Day 1, Day 4, Day 11 and in adult rats. Microdialysis was used to measure concentration ratio of unbound NTF across the BBB (Kp,uu) with or without blockers for active transport (PSC833 and probenecid). To investigate the in vivo contribution of Bcrp, Kp was also measured in Bcrp-/- and wild-type control mice with or without the selective Bcrp blocker Ko143. The Kp decreased with age, but due to an increase in the protein binding. The Kp,uu was on average 0.047 and not affected by the presence of any blocker. Possible explanations for the low Kp,uu is intra-brain metabolism and/or efflux due to other transporter(s). No difference was observed in the Kp of NTF for Bcrp-/- compared to wild-type mice, independent of co-administration with Ko143. Thus, no in vivo contribution of Bcrp to the BBB brain transport of NTF was detected.

Keyword [en]
Blood-brain barrier, development, active transport, Bcrp, nitrofurantoin, intra-brain metabolism, LC-MS/MS
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-109160OAI: oai:DiVA.org:uu-109160DiVA: diva2:249223
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2018-01-13
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: 2018-01-12Bibliographically approved

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