Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin

Abstract

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 À/À 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.

Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats

“…The mRNA levels of each transporter were examined by quantitative real-time PCR. Methods for RNA isolation, cDNA synthesis and real-time PCR have been previously described (Goralski et al, 2003;Teng and Piquette-Miller, 2005;Wang et al, 2005). Briefly, RNA was extracted from tissues by use of the QuickPrep total RNA extraction kit (Amersham, Piscataway, NJ), and singlestranded cDNA was synthesized from 2.5 g of RNA by use of the First Strand cDNA synthesis kit (MBI Fermentas, Hanover, MD) according to the manufacturer's protocol.…”

“…Placental efflux transporters, such as Bcrp and Pgp, are believed to protect placental and fetal tissues by removing potentially toxic xenobiotics and endogenous metabolites. It has been previously demonstrated that endotoxin and other inflammatory stimuli impose a down-regulation of Pgp in epithelial tissues of the liver, intestine, brain, and placenta in rodents (Piquette-Miller et al, 1998;Hartmann et al, 2001;Goralski et al, 2003;Kalitsky-Szirtes et al, 2004;Wang et al, 2005). Recently, it has been reported that intestinal expression of BCRP is decreased in patients with ulcerative colitis (Englund et al, 2007); however, the effect of inflammation on the placental Bcrp expression is unknown.…”

Modulation of P‐glycoprotein activity by cannabinoid molecules in HK‐2 renal cells

“…Initially discovered in tumour cells while investigating the multidrug resistance mechanism, it has been also found and studied in many nontumour cells/tissues (Montano et al, 1996;Smit et al, 1998;Dautrey et al, 1999;Jonker et al, 1999;Gutmann et al, 2000;Florea et al, 2001;Batetta et al, 2003;Cisternino et al, 2003;Goralski et al, 2003;Elliott et al, 2004). P-gp indeed is involved in all pharmacokinetic events (Varma et al, 2003) and many single-nucleotide polymorphisms in the MDR1 gene have been correlated with differences in individual drug responsiveness (Marzolini et al, 2004).…”

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…Out of the 13 TLRs identified in mammals, TLR4 is activated by the gram-negative component, LPS, and TLR2 is activated by the gram-positive component, LTA (Aliprantis et al, 1999;Takeuchi et al, 1999). We and others have shown down-regulation of Cyp3a11 and P-gp in LPS sensitive TLR4 wild type (C3HeB/FeJ) mice could not be detected in TLR4-mutant (C3H/HeJ) mice (Ghose et al, 2008;Goralski et al, 2003;. Recent data from our lab showed that down-regulation of gene expression of key hepatic phase I and phase II DMEs in TLR2 +/+ mice by LTA was blocked in TLR2 -/-mice (Ghose et al, 2009).…”