Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography

S. Eyal, B. Ke, M. Muzi, Jeanne Link, D. A. Mankoff, A. C. Collier, J. D. Unadkat

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)579-585
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume87
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Fingerprint

P-Glycoprotein
Blood-Brain Barrier
Positron-Emission Tomography
Brain
Verapamil
Cyclosporine
Regional Blood Flow
Pharmaceutical Preparations
Healthy Volunteers
White Matter
Gray Matter

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography. / Eyal, S.; Ke, B.; Muzi, M.; Link, Jeanne; Mankoff, D. A.; Collier, A. C.; Unadkat, J. D.

In: Clinical Pharmacology and Therapeutics, Vol. 87, No. 5, 05.2010, p. 579-585.

Research output: Contribution to journalArticle

Eyal, S. ; Ke, B. ; Muzi, M. ; Link, Jeanne ; Mankoff, D. A. ; Collier, A. C. ; Unadkat, J. D. / Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography. In: Clinical Pharmacology and Therapeutics. 2010 ; Vol. 87, No. 5. pp. 579-585.
@article{76a331c159c8403299d51a5c4a305fe6,
title = "Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography",
abstract = "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.",
author = "S. Eyal and B. Ke and M. Muzi and Jeanne Link and Mankoff, {D. A.} and Collier, {A. C.} and Unadkat, {J. D.}",
year = "2010",
month = "5",
doi = "10.1038/clpt.2010.11",
language = "English (US)",
volume = "87",
pages = "579--585",
journal = "Clinical Pharmacology and Therapeutics",
issn = "0009-9236",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography

AU - Eyal, S.

AU - Ke, B.

AU - Muzi, M.

AU - Link, Jeanne

AU - Mankoff, D. A.

AU - Collier, A. C.

AU - Unadkat, J. D.

PY - 2010/5

Y1 - 2010/5

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77951498281&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951498281&partnerID=8YFLogxK

U2 - 10.1038/clpt.2010.11

DO - 10.1038/clpt.2010.11

M3 - Article

VL - 87

SP - 579

EP - 585

JO - Clinical Pharmacology and Therapeutics

JF - Clinical Pharmacology and Therapeutics

SN - 0009-9236

IS - 5

ER -