Age, hypercholesterolemia, and vitamin D deficiency are risk factors that increase the brain accumulation of pathogenic β‐amyloid peptides (40 and 42), precursors leading to Alzheimer's disease (AD) in humans. The relative changes accompanying aging, high cholesterol, and/or treatment of calcitriol, active vitamin D receptor (VDR) ligand, under normal physiology are unknown. We examined these relative changes in C57BL/6 mice of ages 2, 4–8, and more than 10 months old, which were fed a normal or high fat / high cholesterol diet and treated with calcitriol, active ligand of the vitamin D receptor (0 or 2.5 μg/kg ×4, intraperitoneally, every other day to elicit cholesterol lowering in liver). Aβ40 but not Aβ42 accumulation in brain and lower P‐glycoprotein (P‐gp) and neprilysin protein expressions for Aβ efflux and degradation, respectively, were found to be associated with aging. But there was no trend for BACE1 (β‐secretase 1, a cholesterol‐sensitive enzyme) toward Aβ synthesis with age. In response to calcitriol treatment, P‐gp was elevated, mitigating partially the age‐related changes. Although age‐dependent decreasing trends in mRNA expression levels existed for Cyp46a1, the brain cholesterol processing enzyme, whose inhibition increases BACE1 and ApoE to facilitate microglia Aβ degradation, mRNA changes for other cholesterol transporters: Acat1 and Abca1, and brain cholesterol levels remained unchanged. There was no observable change in the mRNA expression of amyloid precursor protein (APP) and the influx (RAGE) and efflux (LRP1) transporters with respect to age, diet, or calcitriol treatment. Overall, aging poses as a risk factor contributing to Aβ accumulation in brain, and VDR‐mediated P‐gp activation partially alleviates the outcome.

Vitamin D 3 and the synthetic vitamin D analogs, 1α-hydroxyvitamin D 3 [1α(OH)D 3 ], 1α-hydroxyvitamin D 2 [1α(OH)D 2 ] and 25-hydroxyvitamin D 3 [25(OH)D 3 ] were appraised for their vitamin D receptor (VDR) associated-potencies as cholesterol lowering agents in mice in vivo. These precursors are activated in vivo: 1α(OH)D 3 and 1α(OH)D 2 are transformed by liver CYP2R1 and CYP27A1 to active VDR ligands, 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and 1α,25-dihydroxyvitamin D 2 [1,25(OH) 2 D 2 ] , respectively. 1α(OH)D 2 may also be activated by CYP24A1 to 1α,24dihydroxyvitamin D 2 [1,24(OH) 2 D 2 ], another active VDR ligand. 25(OH)D 3 , the metabolite formed via CYP2R1 and or CYP27A1 in liver from vitamin D 3 , is activated by CYP27B1 in the kidney to 1,25(OH) 2 D 3 . In C57BL/6 mice fed the high fat/high cholesterol Western diet for 3 weeks, vitamin D analogs were administered every other day intraperitoneally during the last week of the diet. The rank order for cholesterol lowering, achieved via mouse liver small heterodimer partner (Shp) inhibition and increased cholesterol 7α-hydroxylase (Cyp7a1) expression, was: 1.75 nmol/kg 1α(OH)D 3 > 1248 nmol/kg 25(OH)D 3 (dose ratio of 0.0014) > > 1625 nmol/kg vitamin D 3 . Except for 1.21 nmol/kg 1α(OH)D 2 that failed to lower liver and plasma cholesterol contents, a significant negative correlation was observed between the liver concentration of 1,25(OH) 2 D 3 formed from the precursors and liver cholesterol levels. The composite results show that vitamin D analogs 1α(OH)D 3 and 25(OH)D 3 exhibit cholesterol lowering properties upon activation to 1,25(OH) 2 D 3 : 1α(OH)D 3 is rapidly activated by liver enzymes and 25(OH)D 3 is slowly activated by renal Cyp27b1 in mouse. KEYWORDS 1α,25-dihydroxyvitamin D 3 , 1α-hydroxyvitamin D 2 , 1α-hydroxyvitamin D 3 , 25-hydroxyvitamin D 3 , cholesterol 1 | INTRODUCTION 1α,25-Dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the natural and active ligand of the vitamin D receptor (VDR), is formed from the sequential metabolism of vitamin D 3 to 25-hydroxyvitamin D 3 [25(OH)D 3 ] via 25-hydroxylases (microsomal CYP2R1 or mitochondrial CYP27A1) in the liver, then 1α-hydroxylase (CYP27B1) in the kidney. Then 1,25(OH) 2 D 3 is rapidly degraded by the 24-hydroxylase, CYP24A1,to ultimately form calcitroic acid for excretion (Jones, Strugnell, & DeLuca, 1998). Although the VDR is known to regulate plasma calcium (via the absorptive calcium channels TRPV5 and TRPV6) (den Dekker, Hoenderop, Nilius, & Bindels, 2003) and phosphate (Jones et al., 1998) levels, the VDR is also an important regulator of drug transporters and enzymes, including the P-glycoprotein (P-gp) (Chow, Durk,

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.

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