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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [¹¹C]Verapamil

The Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo, Japan (Y.-J. L., H.K., Y.S.); Brain Imaging Project, National Institute of Radiological Sciences, Chiba, Japan (J.M., T.O., M.I., Y.N., S.O., T.S.); and Department of Medical Imaging, National Institute of Radiological Sciences, Chiba, Japan (R.N., K.S.)

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 three rhesus monkeys after intravenous administration of [¹¹C]verapamil under control and P-gp inhibition conditions ([PSC833 ([3'-keto-Me-Bmt¹]-[Val²]-cyclosporin) 20 mg/kg/2 h]). 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 intravenous administration, [¹¹C]verapamil was taken up rapidly into the brain (time to reach the peak, 0.58 min). 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.

Address correspondence to: Dr. Tetsuya Suhara, Brain Imaging Project, National Institute of Radiological Sciences, 9-1, Anagawa 4-Chome, Inage-ku, Chiba 263-8555, Japan. E-mail: suhara{at}nirs.go.jp

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