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 D3 [1,25(OH)2D3], 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)2D3 (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)2D3, confirming that Mdr1/P-gp induction occurred independently of the FXR. Increased P-gp function was evident in 1,25(OH)2D3-treated fxr(+/+) mice given intravenous bolus doses of the P-gp probe, [3H]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)2D3-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.
Footnotes
This work was supported by the Canadian Institutes for Health Research [Grant MOP89850]. E.C.Y.C. was supported by a University of Toronto Open Fellowship and a National Sciences and Engineering Research Council of Canada Alexander Graham Bell Canada Graduate Scholarship. M.R.D. was supported by a Canadian Institutes of Health Research Strategic Training Grant in Biological Therapeutics.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179101.
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ABBREVIATIONS:
- P-gp
- P-glycoprotein
- 1,25(OH)2D3
- 1α,25-dihydroxyvitamin D3
- ASBT
- apical sodium-dependent bile acid transporter
- AUC
- area under the curve
- CL
- clearance
- DDI
- drug-drug interaction
- GAPDH
- glyceraldehyde 3-phosphate dehydrogenase
- FXR
- farnesoid X receptor
- HPLC
- high-pressure liquid chromatography
- MDR1
- multidrug resistance protein 1
- PBPK
- physiologically based pharmacokinetic model
- PMSF
- phenylmethylsulfonyl fluoride
- PXR
- pregnane X receptor
- TBS-T
- Tris-buffered saline with 0.1% Tween 20
- VDR
- vitamin D receptor
- PCR
- polymerase chain reaction
- FR
- fraction reabsorbed
- B/P
- blood/plasma concentration ratio
- GFR
- glomerular filtration rate
- MSC
- model selection criterion.
- Received January 11, 2011.
- Accepted March 16, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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