Doan Trang Nguyen Kieu, Vo Dang-Khoa, Kim Hyojung, Balla Anusha, Lee Yunjong, Yoon In-Soo, Maeng Han-Joo
Department of Pharmacy, College of Pharmacy, Gachon University, Incheon 21936, Korea.
Department of Pharmacology, Sungkyunkwan University School of Medicine, Suwon 16419, Korea.
Pharmaceutics. 2020 Nov 23;12(11):1129. doi: 10.3390/pharmaceutics12111129.
The compound 1α,25-Dihydroxyvitamin D (1,25(OH)D) is the active form of vitamin D and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)D 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)D in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)D 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)D. Consistently, the in vitro metabolic kinetics (V and CL) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)D 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) of BUP were significantly reduced by 1,25(OH)D, 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) of HBUP. Additionally, the AUC, CL, and CL for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)D 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) and lower plasma protein binding in 1,25(OH)D-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)D.
化合物1α,25 - 二羟基维生素D（1,25(OH)D）是维生素D的活性形式，也是维生素D受体（VDR）的代表性配体。以往研究描述了1,25(OH)D对少数细胞色素P450（CYP）和尿苷二磷酸 - 葡萄糖醛酸基转移酶（UGT）的影响，但对于几种重要的CYP和UGT同工型与1,25(OH)D在体外和/或体内的相互作用了解相对较少。因此，我们研究了1,25(OH)D对选定的CYP和UGT的基因和蛋白表达及功能活性的影响，以及它们对大鼠药物药代动力学的影响。1,25(OH)D使大鼠肝脏中Cyp2b1和Cyp2c11的mRNA/蛋白表达下调。一致地，在肝微粒体中，1,25(OH)D处理显著改变了安非他酮（BUP；一种Cyp2b1底物）和甲苯磺丁脲（TOL；一种Cyp2c11底物）的体外代谢动力学（V和CL），但对乙酰氨基酚（一种Ugt1a6/1a7/1a8底物）的动力学没有影响，这与Ugt1a6的蛋白质印迹数据一致。在大鼠药代动力学研究中，1,25(OH)D显著降低了BUP的全身清除率（CL）和非肾清除率（CL），但出乎意料的是，羟基安非他酮（HBUP）从时间零到无穷大的血浆浓度 - 时间曲线下的总面积（AUC）增加，这可能是由于HBUP的肾清除率（CL）显著降低。此外，1,25(OH)D在体内对TOL的AUC、CL和CL以及4 - 羟基甲苯磺丁脲（HTOL）的AUC没有影响。TOL体外代谢活性和体内药代动力学之间的差异可能是由于在1,25(OH)D处理的大鼠中稳态时更大的表观分布容积（V）和更低的血浆蛋白结合率。我们的结果提示了可能的药物 - 药物和药物 - 营养相互作用，并为服用包括1,25(OH)D在内的VDR配体药物的患者提供了有关安全药物组合和给药方案的额外信息。
