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Imaging of Cyclosporine Inhibition of P-Glycoprotein Activity Using ¹¹C-Verapamil in the Brain: Studies of Healthy Humans

¹ Department of Radiology, University of Washington, Seattle, Washington; ² Department of Infectious Disease, University of Washington, Seattle, Washington; and ³ Department of Pharmaceutics, University of Washington, Seattle, Washington

Correspondence: For correspondence or reprints contact: Mark Muzi, Department of Radiology, University of Washington, Box 356004, 1959 NE Pacific St., Seattle, WA 98195-6004. E-mail: muzi{at}u.washington.edu

The multiple-drug resistance (MDR) transporter P-glycoprotein (P-gp) is highly expressed at the human blood–brain barrier (BBB). P-gp actively effluxes a wide variety of drugs from the central nervous system, including anticancer drugs. We have previously demonstrated P-gp activity at the human BBB using PET of ¹¹C-verapamil distribution into the brain in the absence and presence of the P-gp inhibitor cyclosporine-A (CsA). Here we extend the initial noncompartmental analysis of these data and apply compartmental modeling to these human verapamil imaging studies. Methods: Healthy volunteers were injected with ¹⁵O-water to assess blood flow, followed by ¹¹C-verapamil to assess BBB P-gp activity. Arterial blood samples and PET images were obtained at frequent intervals for 5 and 45 min, respectively, after injection. After a 60-min infusion of CsA (intravenously, 2.5 mg/kg/h) to inhibit P-gp, a second set of water and verapamil PET studies was conducted, followed by ¹¹C-CO imaging to measure regional blood volume. Blood flow was estimated using dynamic ¹⁵O-water data and a flow-dispersion model. Dynamic ¹¹C-verapamil data were assessed by a 2-tissue-compartment (2C) model of delivery and retention and a 1-tissue-compartment model using the first 10 min of data (1C₁₀). Results: The 2C model was able to fit the full dataset both before and during P-pg inhibition. CsA modulation of P-gp increased blood–brain transfer (K₁) of verapamil into the brain by 73% (range, 30%–118%; n = 12). This increase was significantly greater than changes in blood flow (13%; range, 12%–49%; n = 12, P < 0.001). Estimates of K₁ from the 1C₁₀ model correlated to estimates from the 2C model (r = 0.99, n = 12), indicating that a short study could effectively estimate P-gp activity. Conclusion: ¹¹C-verapamil and compartmental analysis can estimate P-gp activity at the BBB by imaging before and during P-gp inhibition by CsA, indicated by a change in verapamil transport (K₁). Inhibition of P-gp unmasks verapamil trapping in brain tissue that requires a 2C model for long imaging times; however, transport can be effectively measured using a short scan time with a 1C₁₀ model, avoiding complications with labeled metabolites and tracer retention.

Key Words: verapamil • kinetic modeling • P-glycoprotein • cyclosporine • blood brain barrier

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

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