| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
|
|||||||||
|
|
Neurosciences: Basic ScienceBasic Science Posters |
1 Clinical Imaging Center, GlaxoSmithKline, London, United Kingdom; 2 Center for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada
910
Objectives: P-gp prevents BBB transport of many drugs. Loperamide (Immodium) is a potent opiate agonist widely used for the treatment of diarrhoea. Loperamide does not enter the brain, presumably because it is a substrate for P-gp, and does not exhibit central opiate effects. The goal of this study was to use [11C]loperamide to evaluate its BBB penetrancy under normal conditions and under conditions of decreased P-gp functionality.
Methods: Healthy volunteers were scanned under baseline conditions (n=6) or post administration of the competitive P-gp substrates quinidine (oral, 600mg,n=3) or cyclosporine (IV, 10mg/kg, n=3). Estimates of K1 were obtained using a 1-tissue compartment model using the metabolite corrected arterial input function.
Results: [11C]Loperamide showed very little brain uptake under baseline conditions (K1=0.0021±0.0006 mL.cm-3.min-1). A single oral dose of quinidine did not lead to a significant change in K1 (ratio vs baseline = 1.70±1.24, P=0.24: one-tailed paired t-test). IV administration of cyclosporine led to a two-fold increase in K1 (ratio vs baseline = 2.08±0.63, P=0.047: as before).
Conclusions: Very low CNS delivery was observed for [11C]loperamide under baseline conditions in man. P-gp inhibition led to a modest increase in BBB penetrancy. The low brain uptake and modest effect of P-gp inhibition is consistent with the lack of reported central adverse reactions in man and suggests that, in addition to P-gp, other mechanisms are involved in preventing loperamide central action.
| ||||||||||||||||||||||||||||||||||||||
