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Predicting the Outer Boundaries of P-glycoprotein (P-gp)-Based Drug Interactions at the Human Blood–Brain Barrier Based on Rat Studies

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Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, United States
*(J.D.U.) Phone: (206) 685-2869. Fax: (206) 543-3204. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2014, 11, 2, 436–444
Publication Date (Web):December 23, 2013
Copyright © 2013 American Chemical Society

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    Using positron emission tomography (PET), 11C-verapamil as the P-gp substrate, and cyclosporine A (CsA) as the P-gp inhibitor, we showed that the magnitude of P-gp-based drug interactions at the human blood–brain barrier (BBB) is modest. However, such interactions at clinically relevant CsA blood concentrations may be greater for substrates where P-gp plays an even larger role (fractional contribution of P-gp, ft > 0.97) in preventing the CNS entry of the drug (e.g., nelfinavir). Since we have shown that the rat is an excellent predictor of the verapamil–CsA interaction at the human BBB, we determined the magnitude of drug interaction at the rat BBB between nelfinavir and CsA. Under isoflurane anesthesia, male Sprague–Dawley rats were coadministered IV infusions of nelfinavir and escalating doses of CsA to achieve pseudo steady-state plasma/blood and brain concentrations of both drugs (blood CsA ranged 0–264.9 μM, n = 3–6/group). The percent increase in the brain:blood nelfinavir concentration ratio (determined by LC/MS) was described by the Hill equation with Emax = 6481%, EC50 = 12.3 μM, and γ = 1.6. Then, using these data, as well as in vitro data in LLCPK1 cells expressing the human P-gp, we predicted that CsA (at clinically relevant blood concentration of 1.5 μM) will increase the distribution of nelfinavir into the human brain by 236%. Collectively, our data suggest that clinically significant P-gp based drug interactions at the human BBB are possible for P-gp substrates highly excluded from the brain (ft > 0.97) and should be investigated using noninvasive approaches (e.g., PET).

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