Pharmacokinetics of P‐glycoprotein inhibition in the rat blood‐brain barrier

This article describes the experimental set‐up and pharmacokinetic modeling of P‐glycoprotein function in the rat blood‐brain barrier using [11C]verapamil as the substrate and cyclosporin A as an inhibitor of P‐gp. [11C]verapamil was administered to rats as an i.v. bolus dose followed by graded infusions to obtain steady‐state concentrations in the brain during 70 min. CsA was administered as a bolus followed by a constant infusion 20 min after the start of the [11C]verapamil infusion. The brain uptake of [11C]verapamil over 2 h was portrayed in a sequence of PET scans in parallel with measurement of [11C]verapamil concentrations in blood and plasma and CsA concentrations in blood. Mixed effects modeling in NONMEM was used to build a pharmacokinetic model of CsA‐induced P‐gp inhibition. The brain pharmacokinetics of [11C]verapamil was well described by a two‐compartment model. The effect of CsA on the uptake of [11C]verapamil in the brain was best described by an inhibitory indirect effect model with an effect on the transport of [11C]verapamil out of the brain. The CsA concentration required to obtain 50% of the maximal inhibition was 4.9 µg/mL (4.1 µM). The model parameters indicated that 93% of the outward transport of [11C]verapamil was P‐gp mediated. © 2008 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5386-5400, 2008