title: 1Alpha,25-dihydroxyvitamin D3 up-regulates P-glycoprotein via the vitamin D receptor and not farnesoid X receptor in both fxr(-/-) and fxr(+/+) mice and increased renal and brain efflux of digoxin in mice in vivo.
abstract: Secondary farnesoid X receptor (FXR) effects, in addition to vitamin D receptor (VDR) effects, were observed in the rat liver after treatment with 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the natural ligand of VDR, caused by increased bile acid absorption as a consequence of apical sodium-dependent bile acid transporter induction. To investigate whether the increased multidrug resistance protein 1 (Mdr1)/P-glycoprotein (P-gp) expression in the rat liver and kidney was caused by the VDR and not the FXR, we examined changes in Mdr1/P-gp expression in fxr(+/+) and fxr(-/-) mice after intraperitoneal dosing of vehicle versus 1,25(OH)(2)D(3) (0 or 2.5 μg/kg every other day for 8 days). Renal and brain levels of Mdr1 mRNA and P-gp protein were significantly increased in both fxr(+/+) and fxr(-/-) mice treated with 1,25(OH)(2)D(3), confirming that Mdr1/P-gp induction occurred independently of the FXR. Increased P-gp function was evident in 1,25(OH)(2)D(3)-treated fxr(+/+) mice given intravenous bolus doses of the P-gp probe, [(3)H]digoxin (0.1 mg/kg). Decreased blood (24%) and brain (29%) exposure, estimated as reduced areas under the curve, caused by increased renal (74%) and total body (34%) clearances of digoxin, were observed in treated mice. These events were predicted by physiologically based pharmacokinetic modeling that showed increased renal secretory intrinsic clearance (3.45-fold) and brain efflux intrinsic clearance (1.47-fold) in the 1,25(OH)(2)D(3)-treated mouse, trends that correlated well with increases in P-gp protein expression in tissues. The clearance changes were less apparent because of the high degree of renal reabsorption of digoxin. The observations suggest an important role of the VDR in the regulation of P-gp in the renal and brain disposition of P-gp substrates.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5S 3M2.
authors.forename: Edwin C Y
authors.initials: EC
authors.lastname: Chow
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Durk
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001647:Bile Acids and Salts / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004077:Digoxin / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D014815:Vitamins / Q000494:pharmacology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D002316:Cardiotonic Agents; D004077:Digoxin; D029363:Organic Anion Transporters, Sodium-Dependent; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014807:Vitamin D; D014815:Vitamins; D000099150:Receptor, Farnesoid X-Activated; C118756:dihydroxy-vitamin D3; C071908:sodium-bile acid cotransporter