pgp - publications

Predict more pgp - ligand interactions now!

1. Mol Pharm. 2012 Feb 8. [Epub ahead of print]

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

Hsiao P, Unadkat JD.

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-gp-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,
Emax=2000%, EC50=7.1 µM and γ=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 11C-Lop was
co-administered with a 10 mg/kg i.v. infusion of CsA 1yielding ~5.6 uM CsA blood
concentration) to healthy volunteers, the brain distribution of 11C-radioactivity
was increased by 110% 1. When corrected for diffusible Lop metabolite(s), this
translates into an increase in 11C-Lop brain distribution of 457%. Based on our
rat data, we estimated a remarkably similar value at 5.6 μM 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.

PMID: 22316009 [PubMed - as supplied by publisher]