Differential Effects of 1α,25-Dihydroxyvitamin D3 on the Expressions and Functions of Hepatic CYP and UGT Enzymes and Its Pharmacokinetic Consequences In Vivo

Abstract

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 (Vmax and CLint) 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 (CLNR) 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 (CLR) of HBUP. Additionally, the AUC, CL, and CLNR 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 (Vss) 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.

Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine

“…The metabolic stability of SFN and SFN-NAC was evaluated in human and rat liver microsomes as previously reported [ 23 ], with minor modifications. Briefly, test compounds (1 μM) were incubated with rat and human liver microsomes (final concentration 1 mg/mL protein) containing 1 mM NADPH.…”

Effects of 1α,25-dihydroxyvitamin D3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats

“…For example, 1,25(OH) 2 D 3 administration results in a decrease in rat kidney organic anion transporters (rOAT1/OAT3) expression, leading to a dramatic decrease in renal clearance of cefadroxil and cefdinir (Kim et al 2014). Our recent study also demonstrated that 1,25(OH) 2 D 3 downregulates the mRNA and protein expression of Cyp2b1 and Cyp2c11 in rats, which consequently alters the metabolic function and systemic pharmacokinetics of bupropion and tolbutamide (substrates of Cyp2b1 and Cyp2c11, respectively) (Doan et al 2020). In another recent study of our group, 1,25(OH) 2 D 3 regulated the expression of rat organic cation transporters (rOCT) and rat multidrug and toxin extrusion proteins (rMATE), which was evidenced by a decrease in renal and non-renal (metabolic) clearance of procainamide hydrochloride (an organic cation transporter substrate) and a decrease in the renal clearance of the metabolite N-acetyl procainamide (Balla et al 2021).…”

“…Male Sprague Dawley rats (7-8 weeks old, 220-280 g; Nara Bio Tech., South Korea) were acclimated to laboratory conditions and provided ad libitum access to food and water and maintained under 12-h/12-h light/dark cycles for one week. The treatment of 1,25(OH) 2 D 3 (2.56 nmol/kg/day) was performed as previously reported (Chow et al 2009(Chow et al , 2010Maeng et al 2011;Doan et al 2020;Balla et al 2021). Rats were randomly divided into the control and 1,25(OH) 2 D 3treated groups.…”

“…According to the manufacturer's procedure and a slight modification to optimize the thermal conditions for target genes, the amplification and detection of reaction mixtures were evaluated using the MxPro-Mx3005 software with the following thermal conditions: 95 °C for 10 min, 40 cycles of 95 °C for 15 s, and 56 °C for 30 s, followed by the melting curve. The experiment was carried out using the comparative quantification mode, and the delta-delta method (2 −ΔΔCt ) for relative mRNA quantification was used to calculate the fold expression (Maeng et al 2012;Doan et al 2020;Balla et al 2021). The qPCR primer pairs used were as follows: rGAPDH forward primer 5′-CGC TGG TGC TGA GTA TGT CG-3′; rGAPDH reverse primer 5′-CTG TGG TCA TGA GCC CTT CC-3′; rOCTN1 forward primer 5′-AGC ATT TGT CCT GGG AAC AG-3′; rOCTN1 reverse primer 5′-ACT CAG GGA TGA ACC ACC AG-3′.…”

Pharmacokinetic Drug–Drug Interactions and Herb–Drug Interactions

“…Since 1α,25-dihydroxyvitamin D3 did not inhibit the metabolic activity of bupropion and tobutamide in rat liver microsomes, the decreased metabolic intrinsic clearance of bupropion and tobutamide could be associated with the decreased Cyp2b and Cyp2C expressions. However, the in vitro effect of 1α,25-dihydroxyvitamin D3 on Cyp2b and Cyp2C does not directly translate into the pharmacokinetics of bupropion and tobutamide and their metabolites hydroxybupropion and hydroxytobutamide because of the complicated regulation of 1α,25-dihydroxyvitamin D3 on renal function, protein binding, and other transport activities [ 7 ]. A lack of in vitro and in vivo correlation was also reported by Neag et al [ 8 ].…”