title: Effects of chronic renal failure on brain drug transporters in rats.
abstract: Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.
authors.affiliation: Service de Néphrologie et Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, 5415 boul. de l'Assomption, Montréal, Québec, Canada H1T 2M4.
authors.forename: Judith
authors.initials: J
authors.lastname: Naud
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Laurin
authors.forename: Josée
authors.initials: J
authors.lastname: Michaud
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Beauchemin
authors.forename: Francois A
authors.initials: FA
authors.lastname: Leblond
authors.forename: Vincent
authors.initials: V
authors.lastname: Pichette
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations