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, due to increased bile acid absorption as a consequence of Asbt induction. To investigate whether the increased Mdr1/P-gp expression in the rat liver and kidney was due to VDR and not FXR, we examined changes in Mdr1/P-gp expression in fxr(+/+) and fxr(-/-) mice after intraperitoneal dosing of vehicle vs. 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. Functional increases in P-gp were 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 AUCs, due to increased renal (74%) and total body (34%) clearances of digoxin were observed in treated mice. These events were predicted by physiologically-based pharmacokinetic (PBPK) modeling that showed increased renal secretory intrinsic clearances (3.45-fold) and brain efflux (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 due to high degree of renal reabsorption of digoxin. Nonetheless, 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.
- 1alpha,25-dihydroxyvitamin D3
- P-glycoprotein (MDR1/P-gp)
- farnesoid X receptor (FXR)
- intrinsic clearance
- physiologically-based pharmacokinetic modeling (PBPK)
- vitamin D receptor (VDR)
- Received January 11, 2011.
- Revision received March 14, 2011.
- Accepted March 16, 2011.
- The American Society for Pharmacology and Experimental Therapeutics