Pgp-Mediated Interaction Between (R)-[11C]Verapamil and Tariquidar at the Human Blood-Brain Barrier: A Comparison With Rat Data

被引：96

作者：

Bauer, M. ^{[1
]}

Zeitlinger, M. ^{[1
]}

Karch, R. ^{[2
]}

Matzneller, P. ^{[1
]}

Stanek, J. ^{[1
]}

Jaeger, W. ^{[3
]}

Boehmdorfer, M. ^{[3
]}

Wadsak, W. ^{[4
]}

Mitterhauser, M. ^{[4
]}

Bankstahl, J. P. ^{[5
]}

Loescher, W. ^{[5
]}

Koepp, M. ^{[6
]}

Kuntner, C. ^{[7
]}

Mueller, M. ^{[1
]}

Langer, Oliver ^{[1
,7
]}

机构：

[1] Med Univ Vienna, Dept Clin Pharmacol, Vienna, Austria

[2] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, Vienna, Austria

[3] Univ Vienna, Dept Clin Pharm & Diagnost, Vienna, Austria

[4] Med Univ Vienna, Dept Nucl Med, Vienna, Austria

[5] Univ Vet Med Hannover, Dept Pharmacol Toxicol & Pharm, Hannover, Germany

[6] UCL, Dept Clin & Expt Epilepsy, Inst Neurol, London, England

[7] AIT Austrian Inst Technol GmbH, Hlth & Environm Dept, Mol Med, Seibersdorf, Austria

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2012年 / 91卷 / 02期

基金：

奥地利科学基金会;

关键词：

P-GLYCOPROTEIN FUNCTION; POSITRON-EMISSION-TOMOGRAPHY; SPECIES-DIFFERENCES; INHIBITION; TRANSPORTERS; CYCLOSPORINE; LYMPHOCYTES; METABOLISM; EPILEPSY; XR9576;

D O I：

10.1038/clpt.2011.217

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[C-11] verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[C-11]verapamil brain uptake (expressed as whole-brain volume of distribution (V-T)), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V-T approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V-T relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.

引用

页码：227 / 233

页数：7

共 41 条

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