Imaging of cyclosporine inhibition of P-glycoprotein activity using 11C-verapamil in the brain: studies of healthy humans.
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 (11)C-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 (15)O-water to assess blood flow, followed by (11)C-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 (11)C-CO imaging to measure regional blood volume. Blood flow was estimated using dynamic (15)O-water data and a flow-dispersion model. Dynamic (11)C-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 (1C(10)).


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 (K(1)) 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 K(1) from the 1C(10) model correlated to estimates from the 2C model (r = 0.99, n = 12), indicating that a short study could effectively estimate P-gp activity.


CONCLUSIONS
(11)C-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 (K(1)). 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 1C(10) model, avoiding complications with labeled metabolites and tracer retention.
Muzi
Mark
M
Department of Radiology, University of Washington, Seattle, Washington 98195-6004, USA. muzi@u.washington.edu
Mankoff
David A
DA
Link
Jeanne M
JM
Shoner
Steve
S
Collier
Ann C
AC
Sasongko
Lucy
L
Unadkat
Jashvant D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000328:Adult; D000465:Algorithms; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003198:Computer Simulation; D016572:Cyclosporine / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007089:Image Enhancement / Q000379:methods; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D012016:Reference Values; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014700:Verapamil / Q000493:pharmacokinetics*; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D016572:Cyclosporine; D014700:Verapamil