Document Detail

P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide.
MedLine Citation:
PMID:  20237038     Owner:  NLM     Status:  MEDLINE    
METHODS: Seventeen healthy volunteers had a total of 23 PET scans with (11)C-dLop at baseline and after increasing doses of tariquidar (2, 4, and 6 mg/kg intravenously). A subset of subjects received PET with (15)O-H(2)O to measure cerebral blood flow. Brain uptake of (11)C-dLop was quantified in 2 ways. Without blood data, uptake was measured as area under the time-activity curve in the brain from 10 to 30 min (AUC(10-30)). With arterial blood data, brain uptake was quantified with compartmental modeling to estimate the rates of entry into (K(1)) and efflux from (k(2)) the brain.
RESULTS: Brain uptake of radioactivity was negligible at baseline and increased only slightly (approximately 30%) after 2 mg of tariquidar per kilogram. In contrast, 4 and 6 mg of tariquidar per kilogram increased brain uptake 2- and 4-fold, respectively. Greater brain uptake reflected greater brain entry (K(1)), because efflux (k(2)) and cerebral blood flow did not differ between tariquidar-treated and untreated subjects. In the subjects who received the highest dose of tariquidar (and had the highest brain uptake), regional values of K(1) correlated linearly with absolute cerebral blood flow, consistent with high single-pass extraction of (11)C-dLop. AUC(10-30) correlated linearly with K(1).
CONCLUSION: P-gp function at the blood-brain barrier in humans can be quantified using PET and (11)C-dLop. A simple measure of brain uptake (AUC(10-30)) may be used as a surrogate of the fully quantified rate constant for brain entry (K(1)) and thereby avoid arterial sampling. However, to dissect the function of P-gp itself, both brain uptake and the influx rate constant must be corrected for radiotracer delivery (blood flow).
William C Kreisl; Jeih-San Liow; Nobuyo Kimura; Nicholas Seneca; Sami S Zoghbi; Cheryl L Morse; Peter Herscovitch; Victor W Pike; Robert B Innis
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Publication Detail:
Type:  Clinical Trial; Journal Article; Research Support, N.I.H., Intramural     Date:  2010-03-17
Journal Detail:
Title:  Journal of nuclear medicine : official publication, Society of Nuclear Medicine     Volume:  51     ISSN:  1535-5667     ISO Abbreviation:  J. Nucl. Med.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-03-30     Completed Date:  2010-04-19     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0217410     Medline TA:  J Nucl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  559-66     Citation Subset:  IM    
Molecular Imaging Branch, National Institute of Mental Health, Bethesda, Maryland 20892, USA.
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MeSH Terms
Biological Transport / drug effects
Blood-Brain Barrier / drug effects,  metabolism*,  physiology,  radionuclide imaging
Cerebrovascular Circulation / drug effects
Dose-Response Relationship, Drug
Drug Toxicity
Loperamide / analogs & derivatives*,  metabolism
Magnetic Resonance Imaging
P-Glycoproteins / antagonists & inhibitors,  metabolism*
Positron-Emission Tomography
Quinolines / pharmacology
Radioactive Tracers
Grant Support
Z01 MH002852-04/MH/NIMH NIH HHS
Reg. No./Substance:
0/N-demethylloperamide; 0/P-Glycoproteins; 0/Quinolines; 0/Radioactive Tracers; 53179-11-6/Loperamide; J58862DTVD/tariquidar

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