RT Journal Article
SR Electronic
T1 In Vivo Activation of Human Pregnane X Receptor Tightens the Blood-Brain Barrier to Methadone through P-Glycoprotein Up-Regulation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1212
OP 1219
DO 10.1124/mol.106.023796
VO 70
IS 4
A1 Bauer, Björn
A1 Yang, Xiaodong
A1 Hartz, Anika M. S.
A1 Olson, Emily R.
A1 Zhao, Rong
A1 Kalvass, J. Cory
A1 Pollack, Gary M.
A1 Miller, David S.
YR 2006
UL http://molpharm.aspetjournals.org/content/70/4/1212.abstract
AB The ATP-driven drug export pump, P-glycoprotein, is a primary gatekeeper of the blood-brain barrier and a major impediment to central nervous system (CNS) pharmacotherapy. Reducing P-glycoprotein activity dramatically increases penetration of many therapeutic drugs into the CNS. Previous studies in rat showed that brain capillary P-glycoprotein was transcriptionally up-regulated by the pregnane X receptor (PXR), a xenobiotic-activated nuclear receptor. Here we used a transgenic mouse expressing human PXR (hPXR) to determine the consequences of increased blood-brain barrier P-glycoprotein activity. P-glycoprotein expression and transport activity in brain capillaries from transgenic mice was significantly increased when capillaries were exposed to the hPXR ligands, rifampin and hyperforin, in vitro and when the mice were dosed with rifampin in vivo. Plasma rifampin levels in induced mice were comparable with literature values for patients. We also administered methadone, a CNS-acting, P-glycoprotein substrate, to control and rifampin-induced transgenic mice and measured the drug's antinociceptive effect. In rifampin-induced mice, the methadone effect was reduced by approximately 70%, even though plasma methadone levels were similar to those found in transgenic controls not exposed to rifampin. Thus, hPXR activation in vivo increased P-glycoprotein activity and tightened the blood-brain barrier to methadone, reducing the drug's CNS efficacy. This is the first demonstration of the ability of blood-brain barrier PXR to alter the efficacy of a CNS-acting drug. The American Society for Pharmacology and Experimental Therapeutics