RT Journal Article SR Electronic T1 Highlighting Vitamin D Receptor–Targeted Activities of 1α,25-Dihydroxyvitamin D3 in Mice via Physiologically Based Pharmacokinetic-Pharmacodynamic Modeling JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 75 OP 87 DO 10.1124/dmd.117.077271 VO 46 IS 1 A1 Qi Joy Yang A1 Paola Bukuroshi A1 Holly P. Quach A1 Edwin C. Y. Chow A1 K. Sandy Pang YR 2018 UL http://dmd.aspetjournals.org/content/46/1/75.abstract AB We expanded our published physiologically based pharmacokinetic model (PBPK) on 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], ligand of the vitamin D receptor (VDR), to appraise VDR-mediated pharmacodynamics in mice. Since 1,25(OH)2D3 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 7α-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)2D3. 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 Emax, EC50, and turnover rate constants of VDR-target genes [zero-order production (kin) and first-order degradation (kout) rate constants] showed low coefficients of variation and acceptable median prediction errors (4.5%–40.6%). Sensitivity analyses showed that the Emax and EC50 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)2D3.