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Distribution of zolmitriptan into the CNS in healthy volunteers: a positron emission tomography study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
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2005 (English)In: Drugs in R&D, ISSN 1174-5886, Vol. 6, no 3, 139-147 p.Article in journal (Refereed) Published
Abstract [en]

Objective: Triptans are highly effective in the treatment of migraine. Both central and peripheral mechanisms of action have been suggested. Until now, firm data about the passage of triptans into the CNS in humans have been lacking. The aim of the current study was to evaluate, using positron emission tomography (PET), the uptake and distribution of zolmitriptan into the CNS after intranasal administration. Subjects and methods: Eight healthy volunteers, five males and three females (mean ages 23 and 26 years, respectively), were included. Radioactive [carbonyl-11C]zolmitriptan was infused intravenously for 5 minutes on two occasions: once alone, and once 30–40 minutes after intranasal administration of unlabelled zolmitriptan 5mg. PET was used to measure the concentration of labelled zolmitriptan in the brain, from the start of the tracer infusion for 90 minutes. Regional cerebral blood volume was determined with [15O]carbon monoxide. In addition, an MRI scan was performed to obtain anatomical information. The PET images were analysed quantitatively for different areas of the brain, generating [11C]zolmitriptan time-activity data corrected for circulating tracer activity. The rate of uptake of intranasal zolmitriptan into the CNS was estimated by kinetic modelling using the PET data. Results: PET data from this study demonstrate a rapid dose-proportional uptake of [11C]zolmitriptan into the brain. Significant concentrations of [11C]zolmitriptan were found in all brain regions studied. Calculated CNS concentrations after intranasal zolmitriptan administration showed a gradual increase, reaching about 2nM (0.5 μg/L) 30 minutes after administration and 3.5nM (1.0 μg/L), or one-fifth of the plasma concentration, 1 hour after administration. Five minutes after zolmitriptan administration, the mean CNS concentration had already reached 0.5nM, which is higher than in vitro values for initiation of the agonistic action on 5-HT1B/1D receptors. Conclusion: This study demonstrates by direct measurements that zolmitriptan enters the brain parenchyma in humans, achieving an uptake rate and concentration compatible with a central mode of action.

Place, publisher, year, edition, pages
2005. Vol. 6, no 3, 139-147 p.
Keyword [en]
Administration, Intranasal, Adolescent, Adult, Brain/*metabolism/radionuclide imaging, Carbon Radioisotopes, Dose-Response Relationship; Drug, Female, Humans, Male, Models; Biological, Oxazolidinones/administration & dosage/*pharmacokinetics, Positron-Emission Tomography, Research Support; Non-U.S. Gov't, Serotonin Agonists/administration & dosage/*pharmacokinetics, Tissue Distribution, Tryptamines
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-75659PubMedID: 15869317OAI: oai:DiVA.org:uu-75659DiVA: diva2:103570
Available from: 2006-03-08 Created: 2006-03-08 Last updated: 2014-09-24Bibliographically approved

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Wall, AndersKågedal, MattsJacobsson, EvaAntoni, GunnarLångström, Bengt
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Section of Nuclear Medicine and PETDepartment of Pharmaceutical BiosciencesUCR-Uppsala Clinical Research CenterPreclinical PET PlatformPhysical Organic Chemistry
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