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A novel in vivo receptor occupancy methodology for the glucocorticoid receptor : towards an improved understanding of lung PK/PD
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Boger, Elin, Ewing, P., Eriksson, U. G., Fihn, B.-M., Chappell, M. J. (Michael J.), Evans, Neil D. and Friden, M. (2015) A novel in vivo receptor occupancy methodology for the glucocorticoid receptor : towards an improved understanding of lung PK/PD. Journal of Pharmacology and Experimental Therapeutics, 353 (2). pp. 279-287. doi:10.1124/jpet.114.221226 ISSN 1521-0103.
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Official URL: http://dx.doi.org/10.1124/jpet.114.221226
Abstract
Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of limited possibilities to measure tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library of GR-binders compound 1 was identified to have the properties to be useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography tandem mass spectrometry bio-analysis. The methodology was successfully used to show a dose-relationship for receptor occupancy measured at 1.5 hours after IV-administration of fluticasone propionate (20, 150 and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after an IV-dose of 90 nmol/kg. The dose giving 50% occupancy (ED50) was estimated to 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place post mortem. In addition, the tracer may be labeled for use in positron emission tomography (PET) imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Engineering > Engineering | ||||
| Journal or Publication Title: | Journal of Pharmacology and Experimental Therapeutics | ||||
| Publisher: | American Society for Pharmacology and Experimental Therapeutics | ||||
| ISSN: | 1521-0103 | ||||
| Official Date: | 13 February 2015 | ||||
| Dates: |
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| Volume: | 353 | ||||
| Number: | 2 | ||||
| Page Range: | pp. 279-287 | ||||
| DOI: | 10.1124/jpet.114.221226 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access (Creative Commons) |
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