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Using positron emission tomography (PET), (11)C-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 &gt; 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 &gt; 0.97) and should be investigated using noninvasive approaches (e.g., PET).

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