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Regional P‐Glycoprotein Activity and Inhibition at the Human Blood–Brain Barrier as Imaged by Positron Emission Tomography
Author(s) -
Eyal S,
Ke B,
Muzi M,
Link J M,
Mankoff D A,
Collier A C,
Unadkat J D
Publication year - 2010
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 - 10.1038/clpt.2010.11
Subject(s) - positron emission tomography , cerebral blood flow , white matter , verapamil , p glycoprotein , human brain , blood–brain barrier , medicine , pharmacology , nuclear medicine , endocrinology , neuroscience , chemistry , biology , central nervous system , magnetic resonance imaging , radiology , biochemistry , multiple drug resistance , calcium , antibiotics
We used positron emission tomography (PET) to evaluate the contribution of P‐glycoprotein (P‐gp), present at the human blood–brain barrier (BBB), to regional drug distribution in the brain. Eleven healthy volunteers underwent PET imaging with [ 11 C]‐verapamil before and during cyclosporine A infusion. Regional P‐gp inhibition was expressed as cyclosporine A‐induced percentage change in the distributional clearance of verapamil ( K 1 ) in the brain, normalized to the regional blood flow (rCBF). K 1 estimates were similar across gray‐matter regions of the brain and lower in the white matter regions, but all these estimates were considerably lower than rCBF. Normalization of K 1 by rCBF diminished the differences in estimates related to gray matter and white matter. In contrast, the K 1 for the pituitary, which is situated outside the BBB, approximated the rCBF. The magnitude of P‐gp inhibition was comparable across BBB‐protected brain structures. Our results indicate that P‐gp and its inhibition equally affect the distribution of drugs (and therefore their neuro‐efficacy and toxicity) in the various brain regions protected by the BBB. Clinical Pharmacology & Therapeutics (2010) 87 5, 579–585. doi: 10.1038/clpt.2010.11