Modulation of P-glycoprotein transport activity in the mouse blood-brain barrier by rifampin.
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 approximately 55%, whereas there was only approximately 12% inhibition of P-gp-mediated efflux of quinidine at that rifampin dose. Coperfusion of rifampin at a concentration of 500 microM abolished P-gp-mediated efflux of verapamil at the BBB. However, only approximately 40% inhibition of P-gp-mediated efflux of quinidine was observed with coperfusion of rifampin, even at a 2-fold higher rifampin concentration (1000 microM). 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.
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Jian
J
Zong
Gary M
GM
Pollack
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D010477:Perfusion; D011802:Quinidine / Q000493:pharmacokinetics; D012293:Rifampin / Q000494:pharmacology*; D014700:Verapamil / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000904:Antibiotics, Antitubercular; D014700:Verapamil; D011802:Quinidine; D012293:Rifampin