Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin.
1. Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P-glycoprotein (P-gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P-gp expression and function in the brain and liver. 2. Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When (3)H-digoxin was used at discrete time points, as a probe for P-gp function in vivo, an increase in brain and liver (3)H-radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a(+/+) mice but not in mdr1a(-/-) mice 24 h after administering LPS i.c.v. 3. In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P-gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment. 4. Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P-gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P-gp function in that organ.
Goralski
Kerry B
KB
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
Hartmann
Georgy
G
Piquette-Miller
Micheline
M
Renton
Kenneth W
KW
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001646:Bile / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics*; D015536:Down-Regulation; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism*; D004926:Escherichia coli; D005260:Female; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D027701:Organic Cation Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D008070:Lipopolysaccharides; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; C451262:Slco1c1 protein, rat; D004077:Digoxin; C095122:multidrug resistance protein 3