Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Drug Metab Dispos. 2018 Jan;46(1):75-87. doi: 10.1124/dmd.117.077271. Epub 2017 Oct 30.
We expanded our published physiologically based pharmacokinetic model (PBPK) on 1,25-dihydroxyvitamin D [1,25(OH)D], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)D kinetics was best described by a segregated-flow intestinal model (SFM) that described a low/partial intestinal (blood/plasma) flow to enterocytes, with feedback regulation of its synthesis (Cyp27b1) and degradation (Cyp24a1) enzymes, this PBPK(SFM) model was expanded to describe the VDR-mediated changes (altered/basal mRNA expression) of target genes/responses with the indirect response model. We examined data on 1) renal Trpv5 (transient receptor potential cation channel, subfamily V member 5) and Trpv6 and intestinal Trpv6 (calcium channels) for calcium absorption; 2) liver 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (Hmgcr) and cytochrome 7-hydroxylase (Cyp7a1) for cholesterol synthesis and degradation, respectively; and 3) renal and brain Mdr1 (multidrug-resistance protein that encodes the P-glycoprotein) for digoxin disposition after repetitive intraperitoneal doses of 120 pmol 1,25(OH)D Fitting, performed with modeling software, yielded reasonable prediction of a dominant role of intestinal Trpv6 in calcium absorption, circadian rhythm that is characterized by simple cosine models for Hmgcr and Cyp7a1 on liver cholesterol, and brain and renal Mdr1 on tissue efflux of digoxin. Fitted parameters on the E, EC, and turnover rate constants of VDR-target genes [zero-order production (k) and first-order degradation (k) rate constants] showed low coefficients of variation and acceptable median prediction errors (4.5%-40.6%). Sensitivity analyses showed that the E and EC values are key parameters that could influence the pharmacodynamic responses. In conclusion, the PBPK(SFM)-pharmacodynamic model successfully characterized VDR gene activation and serves as a useful tool to predict the therapeutic effects of 1,25(OH)D.
我们扩展了已发表的维生素 D 受体 (VDR) 配体 1,25-二羟维生素 D [1,25(OH)D] 的基于生理学的药代动力学模型 (PBPK)，以评估 VDR 介导的小鼠药效动力学。由于 1,25(OH)D 动力学最好通过描述低/部分肠道（血液/血浆）流向肠细胞的分离流肠模型 (SFM) 来描述，其合成 (Cyp27b1) 和降解 (Cyp24a1) 酶受到反馈调节，因此该 PBPK(SFM) 模型被扩展为描述 VDR 介导的靶基因/反应的变化（改变/基础 mRNA 表达），采用间接反应模型。我们检查了以下数据：1）肾脏 Trpv5（瞬时受体电位阳离子通道，亚家族 V 成员 5）和 Trpv6 和肠道 Trpv6（钙通道）的钙吸收；2）肝脏 3-羟基-3-甲基-戊二酰基辅酶 A 还原酶 (Hmgcr) 和细胞色素 7-羟化酶 (Cyp7a1) 分别用于胆固醇合成和降解；3）肾脏和大脑 Mdr1（多药耐药蛋白，编码 P-糖蛋白）用于重复腹腔注射 120 pmol 1,25(OH)D Fitting 后地高辛的处置，使用建模软件进行拟合，合理地预测了肠道 Trpv6 在钙吸收中的主导作用，肝脏胆固醇的 Hmgcr 和 Cyp7a1 具有昼夜节律特征，采用简单的余弦模型，地高辛在大脑和肾脏中的组织外排作用由 Mdr1 决定。VDR 靶基因的拟合参数 [零级生产 (k) 和一级降解 (k) 速率常数] 的 E、EC 和周转率常数表明，变异性系数低，中位预测误差可接受（4.5%-40.6%）。敏感性分析表明，E 和 EC 值是影响药效反应的关键参数。总之，PBPK(SFM)-药效学模型成功地描述了 VDR 基因激活，可作为预测 1,25(OH)D 治疗效果的有用工具。
