Abstract

The objective of the present study was to examine the time course and concentration dependence of modulation of P-glycoprotein (P-gp) activity in the blood-brain barrier (BBB) with consequent influence on substrate uptake into brain tissue. Potential P-gp inducers (rifampin and morphine) were administered subchorionically to P-gp-competent [mdr1a(+/+)] mice to induce P-gp expression in brain; the impact of rifampin pretreatment on brain penetration of verapamil also was evaluated with an in situ brain perfusion technique. In addition, the effect of single-dose rifampin on P-gp BBB transport activity was assessed with brain perfusion using verapamil and quinidine as model P-gp substrates. Chronic exposure to rifampin or morphine induced P-gp expression in mouse brain to a modest extent. However, single-dose rifampin treatment increased the brain uptake of verapamil and quinidine in mdr1a(+/+) mice in a dose- and concentration-dependent manner, consistent with P-gp inhibition. Maximum inhibition of P-gp-mediated efflux of verapamil by rifampin pretreatment in vivo (150 mg/kg) was ∼55%, whereas there was only ∼12% inhibition of P-gp-mediated efflux of quinidine at that rifampin dose. Coperfusion of rifampin at a concentration of 500 μM abolished P-gp-mediated efflux of verapamil at the BBB. However, only ∼40% inhibition of P-gp-mediated efflux of quinidine was observed with coperfusion of rifampin, even at a 2-fold higher rifampin concentration (1000 μM). The present studies demonstrate that P-gp function at the BBB can be modulated by rifampin in a dose- and concentration-dependent manner. The degree to which rifampin inhibits P-gp-mediated transport is dependent on the substrate molecule.