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Imaging P‐glycoprotein Transport Activity at the Human Blood‐brain Barrier with Positron Emission Tomography
Author(s) -
Sasongko Lucy,
Link Jeanne M.,
Muzi Mark,
Mankoff David A.,
Yang Xiaodong,
Collier Ann C.,
Shoner Steven C.,
Unadkat Jashvant D.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.01.022
Subject(s) - positron emission tomography , p glycoprotein , blood–brain barrier , tomography , nuclear medicine , medicine , brain positron emission tomography , preclinical imaging , chemistry , radiology , biology , central nervous system , biochemistry , in vivo , microbiology and biotechnology , multiple drug resistance , antibiotics
Background Numerous knockout mouse studies have revealed that P‐glycoprotein (P‐gp) significantly limits drug distribution across the mouse blood‐brain barrier (BBB). To determine the importance of P‐gp at the human BBB, we developed a state‐of‐the‐art, noninvasive, quantitative imaging technique to measure P‐gp activity by use of carbon 11‐labeled verapamil as the P‐gp substrate and cyclosporine (INN, ciclosporin) as the P‐gp inhibitor. Methods In brief, 11 C‐verapamil (approximately 0.2 mCi/kg) was administered to healthy volunteers (n = 12 [6 women and 6 men]) as an intravenous infusion over a period of approximately 1 minute before and after at least a 1‐hour infusion of cyclosporine (2.5 mg · kg −1 · h −1 ). Arterial blood samples and brain positron emission tomography images were obtained at frequent intervals for 45 minutes. Both blood and plasma radioactivity contents were determined in each verapamil sample. The content of verapamil and its metabolites in the 20‐ and 45‐minute plasma samples was determined by a rapid solid‐phase extraction method. The brain uptake of 11 C‐radioactivity (brain area under the curve [AUC brain ]/blood area under the curve [AUC blood ]) was determined in the presence and absence of cyclosporine. Results The AUC brain /AUC blood ratio of 11 C‐radioactivity was increased by 88% ± 20% (1.02 ± 0.18 versus 0.55 ± 0.10, P < .001) in the presence of cyclosporine (mean blood concentration, 2.8 ± 0.4 μmol/L) without affecting 11 C‐verapamil metabolism or plasma protein binding. The corresponding increases for the brain white and gray matter were 84% ± 13% and 84% ± 18%, respectively. Conclusions This is the first time that P‐gp activity at the human BBB has been measured. The modest inhibition of human BBB P‐gp by cyclosporine has implications for P‐gp‐based drug interactions at the human BBB. Our method for imaging P‐gp activity can be used to identify multidrug‐resistant tumors or to determine the contribution of P‐gp polymorphism, inhibition, or induction to interindividual variability in drug response. Clinical Pharmacology & Therapeutics (2005) 77 , 503–514; doi: 10.1016/j.clpt.2005.01.022