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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 17, 2005; DOI: 10.1124/jpet.105.088328

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Received for publication April 22, 2005.
Revised November 15, 2005.
Accepted for publication November 16, 2005.

In vivo evaluation of P-glycoprotein function at the blood-brain barrier in nonhuman primates using [11C]verapamil

Young-Joo Lee 1, Jun Maeda 2, Hiroyuki Kusuhara 1, Takashi Okauchi 2, Motoki Inaji 2, Yuji Nagai 2, Shigeru Obayashi 2, Ryuji Nakao 2, Kazutoshi Suzuki 2, Yuichi Sugiyama 3, Tetsuya Suhara 2*

1 University of Tokyo 2 National Institute of Radiological Sciences 3 The University of Tokyo

* Address correspondence to: E-mail: suhara{at}nirs.go.jp

Abstract

P-glycoprotein (P-gp) is a major efflux transporter contributing to the efflux of a range of xenobiotic compounds at the blood-brain barrier (BBB). In the present study, we evaluated the P-gp function at the BBB using positron emission tomography (PET) in nonhuman primates. Serial brain PET scans were obtained in 3 rhesus monkeys after intravenous administration of [11C]verapamil under control and P-gp inhibition conditions (PSC833, 20mg/kg/2hr). The parent [11C]verapamil and its metabolites in plasma were determined by HPLC with a positron detector. The initial brain uptake clearance calculated from the integration plot was used for the quantitative analysis. After intra-venous administration, [11C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58min). The blood level of [11C]verapamil decreased rapidly and it underwent metabolism with time. The inhibition of P-gp by PSC833 increased the brain uptake of [11C]verapamil 4.61-fold (0.141 versus 0.651 ml/g brain/min, p < 0.05). These results suggest that PET measurement with [11C]verapamil can be used for the evaluation of P-gp function at the BBB in the living brain.


Key words: P-glycoprotein, PSC833, Positron emission tomography, blood-brain barrier, efflux transport, verapamil


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