The compound 1α,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) is the active form of vitamin D₃ and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)₂D₃ on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)₂D₃ in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)₂D₃ on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)₂D₃. Consistently, the in vitro metabolic kinetics (V_max and CL_int) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)₂D₃ treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CL_NR) of BUP were significantly reduced by 1,25(OH)₂D₃, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CL_R) of HBUP. Additionally, the AUC, CL, and CL_NR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)₂D₃ in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (V_ss) and lower plasma protein binding in 1,25(OH)₂D₃-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)₂D₃.

#	Concept	H-Index	Publications	Citations
1	Medicine	2	2	35
2	Pharmacology	2	2	35
3	Engineering	1	1	19
4	Biochemistry	1	1	16
5	Metabolism	1	1	16

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