P-Glycoprotein-Based Loperamide-Cyclosporine Drug Interaction at the Rat Blood-Brain Barrier: Prediction from In Vitro Studies and Extrapolation to Humans

We have shown that the rat can quantitatively predict the verapamil-cyclopsorine A (CsA) drug drug interaction (DDI) at the human blood brain barrier (BBB). In addition, the potency (EC50) of CsA to inhibit rat BBB P-gp can be predicted from in vitro studies in MDRI-transfected cells. To assess if these excellent agreements extend to other substrates, we determined the magnitude of P-E;p-based DDI at the rat BBB between loperamide (Lop) or its metabolite, N-desmethyl Lop (dLop), and escalating CsA blood concentrations. The percent increase in the brain:blood Lop concentration ratio was described by the Hill equation, E-max = 2000%, EC50 = 7.1 mu M and gamma=3.7. The potency (EC50) of CsA to inhibit P-gp at the rat BBB was independent of the substrate used (verapamil, Lop, or dLop). Like the verapamil CsA DDI, the potency (EC50) of CsA to inhibit rat BBB P-gp could be predicted from studies in MDRI-transfected cells. When C-11-Lop was coadministered with a 10 mg/kg iv infusion of CsA(1)yielding similar to 5.6 uM CsA blood concentration to healthy volunteers, the brain distribution of C-11-radioactivity was increased by 110%(1) When corrected for diffusible Lop metabolite(s), this translates into an increase in C-11-Lop brain distribution of 457%. Based on our rat data, we estimated a similar value at 5.6 mu M blood CsA concentration, 588% increase in Lop brain distribution. These data support our conclusion that the rat is a promising model to predict P-gp based DDI at the human BBB.