P346 Quantification of P-glycoprotein Inhibition by Quinidine at the Human Blood-Brain Barrier Using Positron Emission Tomography Imaging

Li Liu , Pharmaceutics, University of Washington, Seattle, WA
Permeability-glycoprotein (P-gp), an efflux transporter at the Blood-Brain Barrier (BBB), is believed to be one of the primary obstacles for the brain delivery of CNS drugs.  The functional importance of P-gp at the human BBB was first demonstrated via Positron Emission Tomography (PET) imaging using a model P-gp inhibitor (cyclosporine-A), which produced 79% increase in the brain uptake of P-gp radiolabeled substrate, 11C-verapamil1.  However, we questioned if CsA represents the maximum P-gp inhibitory interaction.  Therefore, this PET study was conducted to further evaluate and quantify the maximum level and clinical significance of P-gp inhibition achievable at the human BBB using a FDA-approved drug and more potent P-gp inhibitor, quinidine.  7 healthy volunteers (4 women and 3 men) were administered 11C-verapamil (~0.2 mCi/kg) intravenously before and after 1 hour of quinidine IV infusion (0.153 mg/kg/min).  During each PET-imaging session, frequent arterial blood and plasma samples were obtained to determine the total radioactivity content.  11C-verapamil parent and metabolites radioactivity were quantified via rapid solid-phase extraction-LCUV2.    The tissue uptake (AUCtissue/plasma ratio), distribution clearance (K1) and extraction ratio (ER) of 11C-radioactivity for the brain, gray and white matter during the first 10 mins were determined in the presence and absence of quinidine, and compared using the Student’s paired t-test.  In the presence of quinidine (mean total plasma concentration of 3.08±0.43 µg/mL), significant increases in the AUC(tissue/plasma) ratios were observed for the brain (84.4±42.0%), gray matter (83.7±42.4%), and white matter (87.2±42.7%) with p-values<0.005. Quinidine did not affect the extent of 11C-verapamil metabolism.  A 2-tissue compartment model using a single input function of total plasma radioactivity was determined to be the best model for estimating K1 and ER.  In the presence of quinidine, the average K1 and ER estimates were significantly increased (p-values<0.05) for the brain (78.1±67.5%, 69.5±65.3%), gray matter (68.2±40.3%, 84.7±81.2%) and white matters (93.7±76.4%, 70.5±89.5%).  Our results demonstrated that P-gp activity at the human BBB was significantly inhibited by quinidine.  Our findings suggest that quinidine can produce adverse drug-drug interactions at the human BBB with CNS agents that are P-gp substrates, and exhibit narrow therapeutic windows.  However, at its therapeutic concentrations, quinidine is unlikely to produce maximum P-gp inhibition at the human BBB, and is also unlikely to be a clinically effective P-gp inhibitor that can produce robust increase in the brain delivery of CNS drugs.  Therefore, additional investigations using more potent and FDA-approved P-gp inhibitors are needed to quantify the maximum level of P-gp inhibition at the human BBB, and to confirm the utility of P-gp inhibition in improving CNS drug therapy. 

Supported by 1RCNS06804

  1. Sasongko L, Link JM, Muzi M, Mankoff DA, Yang X, Collier AC, Shoner SC, Unadkat JD. Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther. 77(6):503-14. 2005
  2. Unadkat JD, Chung F, Sasongko L, Whittington D, Eyal S, Mankoff D, Collier AC, Muzi M, Link J. Rapid solid-phase extraction method to quantify [(11)C]-verapamil, and its [(11)C]-metabolites, in human and macaque plasma. Nucl Med Biol. 35(8):911-7. 2008