Modulation of P-glycoprotein Transport Activity in the Mouse Blood-Brain Barrier by Rifampin
- 29 April 2003
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Journal of Pharmacology and Experimental Therapeutics
- Vol. 306 (2), 556-562
- https://doi.org/10.1124/jpet.103.049452
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 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.Keywords
This publication has 26 references indexed in Scilit:
- Development of an In Situ Mouse Brain Perfusion Model and its Application to mdr1a P-Glycoprotein-Deficient MiceJournal of Cerebral Blood Flow & Metabolism, 2000
- The role of intestinal P-glycoprotein in the interaction of digoxin and rifampinJCI Insight, 1999
- BIOCHEMICAL, CELLULAR, AND PHARMACOLOGICAL ASPECTS OF THE MULTIDRUG TRANSPORTERAnnual Review of Pharmacology and Toxicology, 1999
- Stimulation of P‐glycoprotein‐mediated drug transport by prazosin and progesteroneEuropean Journal of Biochemistry, 1999
- HIV-1 Protease Inhibitors Are Substrates for theMDR1 Multidrug TransporterBiochemistry, 1998
- The physiological function of drug-transporting P-glycoproteinsSeminars in Cancer Biology, 1997
- Potentiation of Pirarubicin Activity in Multidrug Resistant Cells by Rifampicin.Biological & Pharmaceutical Bulletin, 1997
- Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver diseaseCell, 1993
- BIOCHEMISTRY OF MULTIDRUG RESISTANCE MEDIATED BY THE MULTIDRUG TRANSPORTERAnnual Review of Biochemistry, 1993
- A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutantsBiochimica et Biophysica Acta (BBA) - Biomembranes, 1976