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Verapamil P-glycoprotein Transport across the Rat Blood-Brain Barrier: Cyclosporine, a Concentration Inhibition Analysis, and Comparison with Human Data

To predict the magnitude of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier (BBB), rodent studies are routinely conducted where P-gp is chemically inhibited. For such studies to be predictive of interactions at the human BBB, the plasma concentration of the P-gp inhibi...

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Published in:The Journal of pharmacology and experimental therapeutics 2006-05, Vol.317 (2), p.704-710
Main Authors: Hsiao, Peng, Sasongko, Lucy, Link, Jeanne M, Mankoff, David A, Muzi, Mark, Collier, Ann C, Unadkat, Jashvant D
Format: Article
Language:English
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Summary:To predict the magnitude of P-glycoprotein (P-gp)-based drug interactions at the human blood-brain barrier (BBB), rodent studies are routinely conducted where P-gp is chemically inhibited. For such studies to be predictive of interactions at the human BBB, the plasma concentration of the P-gp inhibitor must be comparable with that observed in the clinic. Therefore, we determined the in vivo EC 50 of P-gp inhibition at the rat BBB using verapamil as a model P-gp substrate and cyclosporine A (CsA) as the model P-gp inhibitor. Under isoflurane anesthesia, male Sprague-Dawley rats were administered i.v. CsA to achieve pseudo steady-state CsA blood concentrations ranging from 0 to ∼12 μM. Then, an i.v. tracer dose of [ 3 H]verapamil was administered, and 20 min after verapamil administration, the animals were sacrificed for determination of blood, plasma, and brain 3 H radioactivity by scintillation counting. The percentage increase in the brain/blood 3 H radioactivity (relative to 0 μM CsA) was described by the Hill equation with E max , 1290%; EC 50 , 7.2 μM; and γ, 3.8. Previously, using [ 11 C]verapamil, we have shown that the human brain/blood 11 C radioactivity was increased by 79% at 2.8 μM CsA blood concentration. At an equivalent CsA blood concentration, the rat brain/blood 3 H radioactivity was increased by a remarkably similar extent of 75%. This is the first time that an in vivo CsA EC 50 of P-gp inhibition at the rat BBB has been determined and the magnitude of such inhibition was compared between the rat and the human BBB at the same blood CsA concentration.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.105.097931