Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans.
Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans.
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DOI：
10.2967/jnumed.108.059162
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发表时间：
2009-08
期刊：
影响因子：
--
通讯作者：
Unadkat JD
中科院分区：
文献类型：
--
作者：
Muzi M;Mankoff DA;Link JM;Shoner S;Collier AC;Sasongko L;Unadkat JD
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. 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). 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. 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.
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影响因子：
5.7
作者：
Bart, J;Willemsen, ATM;Hendrikse, NH
通讯作者：
Hendrikse, NH
影响因子：
6.3
作者：
Lubberink, Mark;Luurtsema, Gert;Lammertsma, Adriaan A.
通讯作者：
Lammertsma, Adriaan A.
影响因子：
6.3
作者：
LAMMERTSMA, AA;BROOKS, DJ;JONES, T
通讯作者：
JONES, T
DOI：
10.1124/jpet.103.049452
发表时间：
2003-08-01
影响因子：
3.5
作者：
Zong, J;Pollack, GM
通讯作者：
Pollack, GM
影响因子：
6.3
作者：
LOGAN, J;FOWLER, JS;CHRISTMAN, DR
通讯作者：
CHRISTMAN, DR