Highlighting Vitamin D Receptor–Targeted Activities of 1α,25-Dihydroxyvitamin D₃in Mice via Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling

Abstract

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.

Potencies of vitamin D analogs, 1α‐hydroxyvitamin D3, 1α‐hydroxyvitamin D2 and 25‐hydroxyvitamin D3, in lowering cholesterol in hypercholesterolemic mice in vivo

“…Although mouse renal Trpv6 mRNA expression levels were significantly increased following 25(OH)D 3 , 1α(OH)D 3 and 1α(OH)D 2 treatment, ileal Trpv6 mRNA levels remained unchanged (Table ). Yang et al () as well as others have made the assertion that the intestinal Trpv6 and not renal Trpv6 nor Trpv5 is the important component for calcium absorption. Mice that were given the low dose of 1α(OH)D 3 showed smaller changes in body weight, ALT and plasma calcium levels when compared with 1,25(OH) 2 D 3 (Table ) and avoided the toxic effects observed with the higher doses of 1α(OH)D 3 used by Chow, Durk, et al ().…”

“…In contrast, the mouse liver contains measurable Vdr protein expression (Chow et al, ; Chow, Durk, Maeng, & Pang, ) and 1,25(OH) 2 D 3 treatment could lead to increased mRNA and protein expression of Cyp7a1 and cholesterol lowering (Chow, Quach, et al, ). However, the utility of 1,25(OH) 2 D 3 may be limited due to hypercalcemia (Chow et al, ; Chow, Quach, et al, ; Yang, Bukuroshi, Quach, Chow, & Pang, ). Thus, vitamin D analogs that do not exhibit this toxic side effect would be more desirable as therapeutic agents for hypercholesterolemia.…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…Exogenous factors are drug‐dependent, including the physicochemical properties of the drug that impact ADME, such as MW, pKa, and log P. When predicting DDI, the properties of a perpetrator (k i , K I , k inact for inhibition, E max and EC 50 for induction) or a victim ( in vivo elimination pathways, in vitro f m of metabolism or clearance) are included, as well as the turnover rates (k deg ) of the target enzymes or transporters. For case studies of PBPK modeling that are used to advance drug candidates, please refer to references on regulatory guidance, research, and review articles from industry and academia (https://www.fda.gov/regulatory‐information/search‐fda‐guidance‐documents/physiologically‐based‐pharmacokinetic‐analyses‐format‐and‐content‐guidance‐industry, https://www.ema.europa.eu/en/documents/scientific‐guideline/guideline‐reporting‐physiologically‐based‐pharmacokinetic‐pbpk‐modelling‐simulation_en.pdf, Li, Kimoto, et al, ; Li, Niosi, et al, ; Sager, Yu, Ragueneau‐Majlessi, & Isoherranen, ; Wagner, Pan, Hsu, Sinha, & Zhao, ; Yang, Bukuroshi, Quach, Chow, & Pang, ; Yao, Toshimoto, Kim, Yoshikado, & Sugiyama, ; Zhao, Rowland, & Huang, ; Zhuang & Lu, ).…”

Noteworthy idiosyncrasies of 1α,25‐dihydroxyvitamin D3 kinetics for extrapolation from mouse to man: Commentary

“…and i.p. injection of calcitriol are adequately described by the indirect‐response models (Equations 6 and 7) that inhibited renal Cyp27b1 synthesis but stimulated Cyp24a1 synthesis in tissues (kidney, liver, brain, and intestine) (Quach et al, 2015; Ramakrishnan et al, 2016; Yang, Bukuroshi, Quach, Chow, & Pang, 2018).…”

“…A trend could be identified in humans, for example, in patients with CKD, or cancer. PBPK modeling is a prerequisite for a comprehensive understanding of calcitriol pharmacokinetics on circulating calcitriol concentrations and their associated toxicity (hypercalcemia) (Yang et al, 2018) and we are able to predict the complex regulatory mechanisms of calcitriol and pharmacokinetics. The approach is particularly useful during disease conditions to embellish the changes in enzymes or transporters.…”