Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.

CYP11A1 and CYP27A1 hydroxylate tachysterol3 , a photoproduct of previtamin D3 , producing 20S-hydroxytachysterol3 [20S(OH)T3 ] and 25(OH)T3 , respectively. Both metabolites were detected in the human epidermis and serum. Tachysterol3 was also detected in human serum at a concentration of 7.3 ± 2.5 ng/ml. 20S(OH)T3 and 25(OH)T3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]. They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR coupled GFP from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay system revealed marked activation of AhR by 20S(OH)T3 , a smaller effect by 25(OH)T3 , and a minimal effect for their precursor, tachysterol3 . Tachysterol3 hydroxyderivatives showed high-affinity binding to the ligan-binding domain (LBD) of the liver X receptor (LXR) α and ß, and the peroxisome proliferator-activated receptor γ (PPARγ) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs, and PPARγ revealed high docking scores for 20S(OH)T3 and 25(OH)T3 , comparable to their natural ligands. The scores for the non-genomic-binding site of the VDR were very low indicating a lack of interaction with tachysterol3 ligands. Our identification of endogenous production of 20S(OH)T3 and 25(OH)T3 that are biologically active and interact with VDR, AhR, LXRs, and PPARγ, provides a new understanding of the biological function of tachysterol3 .

Vitamin D kinetics in nonpregnant and pregnant women after a single oral dose of trideuterated vitamin D3.

The plasma pool of the hormone 1,25-dihydroxyvitamin D (1,25(OH)2D) is increased throughout most of human pregnancy. Mechanisms behind this adaptation are unclear, in part due to limited data on vitamin D kinetics during pregnancy. Stable isotopes make it possible to study vitamin D kinetics in vulnerable study populations like pregnant women. We conducted a pilot study of vitamin D kinetics in nonpregnant and pregnant women. We evaluated a clinical protocol and developed analytical methods to assess the serum appearance and disappearance of trideuterated vitamin D3 (d3-vitamin D3) and trideuterated 25-hydroxyvitamin D3 (d3-25(OH)D3) after a single oral dose of 25 µg of [6,19,19-2H]-vitamin D3 (d3-vitamin D3). Blood was collected at baseline and 2, 4, 6, 24, 168, 264, and 456 hours post-dosing. We then described the serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 in nonpregnant and pregnant women. Serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 followed a time course in line with previous pharmacokinetic studies. There was marked variability between participants in the area under the concentration-time curve (AUC) of d3-25(OH)D3 over the 20-day study period. This AUC of d3-25(OH)D3 was positively correlated with the serum vitamin D binding protein (DBP) concentration, which was higher in pregnant compared with nonpregnant women. The mean serum half-life of 25(OH)D3 was longer but not significantly different in pregnant women (18.8 days) compared with nonpregnant women (13.6 days). Our pilot study demonstrated that a single oral dose of 25 µg of d3-vitamin D3 can be used to study vitamin D kinetics. Serum DBP concentration is an important predictor of vitamin D kinetics, and more research is needed to fully understand the significance of elevated DBP concentration during pregnancy.

Bioequivalence for a Fixed-Dose Combination Formulation of Bazedoxifene and Cholecalciferol Compared With the Corresponding Single Entities Given Together.

A fixed-dose combination (FDC) formulation of bazedoxifene 20 mg and cholecalciferol 8 mg was developed to increase medication compliance and convenience for osteoporosis patients. This study was conducted to demonstrate bioequivalence by comparing the pharmacokinetic (PK) profiles and tolerability of an FDC tablet and the individual component tablets. A randomized, open-label, single-dosing, 2-treatment, 2-period, 2-sequence crossover study was conducted in 52 healthy subjects. All subjects were randomly assigned to 2 sequences, and they received FDC tablets of bazedoxifene and cholecalciferol and individual component tablets. Serial blood samples for PK evaluation were collected up to 24 hours predose and 120 hours postdose, and the PK parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. Of the enrolled 52 subjects, 47 subjects completed the study. The results, the geometric mean ratios (GMRs) and 90% confidence intervals (90%CIs), of bazedoxifene Cmax and AUC0-t for FDC to single entities given together were 0.98 (0.91-1.05) and 1.02 (0.97-1.07), respectively. The GMRs (90%CIs) of cholecalciferol Cmax and AUC0-t for FDC to single entities given together were 0.96 (0.91-1.00) and 0.94 (0.90-0.99), respectively. Overall, the GMRs (90%CIs) of the PK parameter of bazedoxifene and cholecalciferol fell within the conventional bioequivalence range of 0.8-1.25. There were no clinically significant differences in the safety profile between the 2 treatments. In conclusion, this study confirmed the development of a new FDC drug by demonstrating that the FDC formulation of bazedoxifene and cholecalciferol is biologically equivalent to the coadministered individual formulations.

Mechanisms of absorption of vitamin D3 delivered in protein nanoparticles in the absence and presence of fat.

Novel protein-based nanovehicles offer alternatives to fat for delivery of lipophilic bioactives (nutraceuticals and drugs), yet they raise important questions regarding the bioavailability and absorption mechanism of the bioactive without fat. To provide answers, we chose vitamin D3 (VD3) as a model lipophilic-nutraceutical, re-assembled casein-micelles (rCM) as model protein-based nanovehicles, and non-fat yoghurt as a model food. We prepared three yoghurt formulations: 3% fat with VD3 dissolved in milk-fat, non-fat and 3% fat, both latter enriched with VD3 within rCM. Following in vitro digestion, VD3 retention and bioaccessibility were high (∼90% and ∼70%, respectively) in all formulations. VD3 uptake by Caco-2 cells was three-fold higher (p < 0.005) in the non-fat yoghurt enriched with VD3 in rCM compared with enriched fat-containing yoghurts. SR-BI, CD36 and NPC1L1 transporters were involved in VD3 absorption irrespective of the composition. Thus, our findings demonstrate that protein nanovehicles may improve VD3 bioavailability, without altering its absorption mechanism compared to that from fat.

A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption.

BACKGROUND: Obese and malabsorptive patients have difficulty increasing serum 25-hydroxyvitamin D [25(OH)D] after taking vitamin D supplementation. Since 25(OH)D is more hydrophilic than vitamin D, we hypothesized that oral 25(OH)D supplementation is more effective in increasing serum 25(OH)D concentrations in these patients. OBJECTIVES: We aimed to investigate the pharmacokinetics of oral 25-hydroxyvitamin D3 [25(OH)D3] and oral vitamin D3 in healthy participants with differing BMI and malabsorptive patients. METHODS: A randomized, double-blind crossover trial was performed in 6 malabsorptive patients and 10 healthy participants who were given 900 µg of either vitamin D3 or 25(OH)D3 orally followed by a pharmacokinetic study (PKS). After ≥28 d from the first dosing, each participant returned to receive the other form of vitamin D and undergo another PKS. For each PKS, serum vitamin D3 and 25(OH)D3 were measured at baseline and at 2, 4, 6, 8, and 12 h and days 1, 2, 3, 7, and 14. Pharmacokinetic parameters were calculated. RESULTS: Data were expressed as means ± SEMs. The PKS of 900 µg vitamin D3 revealed that malabsorptive patients had 64% lower AUC than healthy participants (1177 ± 425 vs. 3258 ± 496 ng · h/mL; P < 0.05). AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.540). The 10 healthy participants were ranked by BMI and categorized into higher/lower BMI groups (5/group). The PKS of 900 µg vitamin D3 showed that the higher BMI group had 53% lower AUC than the lower BMI group (2089 ± 490 vs. 4427 ± 313 ng · h/mL; P < 0.05), whereas AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.500). CONCLUSIONS: Oral 25(OH)D3 may be a good choice for managing vitamin D deficiency in malabsorption and obesity. This trial was registered at clinicaltrials.gov as (NCT03401541.

The impact of emulsion droplet size on in vitro lipolysis rate and in vivo plasma uptake kinetics of triglycerides and vitamin D3 in rats.

Emulsions play an important role in the process of triglyceride (TG) digestion (lipolysis). Through emulsification, the oil-water interface is increased by orders of magnitude. This often leads to faster and more efficient lipolysis, which is potentially beneficial for the intestinal uptake of oils and lipophilic compounds. In this paper, we first examined the effect of emulsion droplet size on the in vitro lipolysis rate. Then an in vivo experiment was performed, to examine the plasma uptake kinetics of TGs and vitamin D3 (vitD3) over a 24 hours period after oral administration of the emulsions in rats. Basic corn oil emulsions loaded with vitD3 were prepared using polysorbate 80 as the emulsifier, with three different droplet sizes (D[3,2]): ∼3 µm (large), ∼1 µm (medium) and ∼0.3 µm (small). In vitro lipolysis experiments showed, as expected, that smaller droplets were lipolyzed more rapidly. However, the medium emulsion had by far the highest rate of lipolysis per surface area. This was attributed to bile salt limitation, polysorbate 80 lipolysis inhibition and TG digestion product accumulation. In vivo, the two smallest emulsions showed the highest uptake (Cmax and AUC) of vitD3 and TG, while the largest emulsion and bulk oil control showed lower values. However, only the (incremental) TG plasma values and kinetics displayed some statistically significant differences. These findings may have relevance for the formulation of functional foods/beverages or delivery units containing oils or lipophilic bioactives.

Effect of 1-year oral cholecalciferol on a metabolic profile and blood pressure in poor-controlled type 2 diabetes mellitus: an open-label randomized controlled pilot study.

PURPOSE: Hypovitaminosis D has been associated with many cardio-metabolic disorders, although their pathogenetic link still remains unclear. Our aim was to evaluate whether 1-year vitamin D (D) supplementation could improve glycemic control, lipid profile, systolic (SBP) and diastolic (DBP) blood pressure levels and body composition. METHODS: In an open-label randomized-controlled pilot study, thirty poor-controlled (HbA1c > 59 mmol/mol) type 2 diabetic patients (age 71.5 ± 3.2 years, M/F 21/9, BMI 29.8 ± 3.6 kg/m2) with hypovitaminosis D (25OHD 22.0 ± 11.3 nmol/l) were randomized to cholecalciferol supplementation (500 UI/kg p.o. weekly, + D) or observation (- D) for one year. Changes in parameters of glucose, lipid and blood pressure control at 3, 6, 9 and 12 months vs. baseline were assessed. RESULTS: One-year D supplementation restored D status and had a beneficial effect on fasting glucose (FG, mean percentage changes ± SD, - 1.8% ± 23.1 vs. + 18.8% ± 30.0), glycosylated haemoglobin (HbA1c, - 13.7% ± 14.5 vs. - 4.2% ± 14.1), SBP (- 13.4% ± 8.5 vs. - 2.4% ± 12.6) and HDL-cholesterol levels (- 2.1% ± 14.0 vs. - 10.9% ± 12.9; p < 0.05 for all comparisons) in + D vs. - D patients, respectively. In the former, a reduction in HBA1c, SBP and DBP levels, BMI, fat mass index (FMI) and ratio (FMR) was observed after 1 year (p < 0.05 for all comparisons vs. baseline). We noticed a relationship between 1-year mean percentage changes of serum 25OHD and SBP levels (R = - 0.36, p < 0.05). CONCLUSION: One-year cholecalciferol supplementation, able to restore D status, significantly improves FG, HbA1c, SBP and HDL-cholesterol levels in patients with poor-controlled type 2 diabetes mellitus and D deficiency.

Vitamin D3 bioaccessibility: Influence of fatty acid chain length, salt concentration and l-α-phosphatidylcholine concentration on mixed micelle formation and delivery of vitamin D3.

Vitamin D (VD) is a fat-soluble vitamin with high deficiency levels evident globally. Bioaccessibility of VD is influenced by formation of mixed micelles (MM) during digestion. This study assessed the impact of fatty acid (FA) type, phospholipid concentration on MM formation and stability of MM to salts. MM formation occurred at NaCl and KCl concentrations ranging from 20 to 100 mM, when octanoic acid (C8) or stearic acid (C18) were used. MM hydrodynamic size increased with increasing l-α-phosphatidylcholine concentration (1.5-7.5 mM) for both C8 and C18, above which concentration MM did not form. FA chain length impacted MM with hydrodynamic size increasing from 3.8 nm for decanoic acid (C10) to 4.4 nm for C18. VD3 incorporation in MM was not influenced by the FA used (C10 or C18). Understanding stability and formation of MM and VD3 loading is an essential first step towards manipulating food structures for improving delivery of VD.

Differential effects of vitamin D3 vs vitamin D2 on cellular uptake, tissue distribution and activation of vitamin D in mice and cells.

To combat vitamin D deficiency, vitamin D3 and vitamin D2 are commonly used as a supplement or to fortify food sources. Human data show that the response of 25-hydroxyvitamin D (25(OH)D) to supplementation with vitamin D3 is higher than to vitamin D2. To elucidate the metabolic route of both vitamers, we conducted a study with vitamin D-depleted mice, which were allotted into three groups (n = 12) and received equal doses of either deuterated vitamin D3, deuterated vitamin D2 or both for 4 weeks. To further investigate the hepatic uptake and hydroxylation of both D-vitamers to 25(OH)D, we conducted cell culture experiments with murine and human hepatoma cells (Hepa1-6 and HepG2). The vitamin D metabolite concentrations in serum, tissues and cells were analyzed by LC-MS/MS or ELISA. In mice, vitamin D2 resulted in lower serum and tissue concentrations of vitamin D (P < 0.001) than vitamin D3, while the group which received both D-vitamers showed values in between. Interestingly, vitamin D2 fed mice had 1.9-times and 2.9-times higher serum concentrations of total and free 25(OH)D (P < 0.001) than mice fed vitamin D3, while the concentration of 1,25-dihydroxyvitamin D (1,25(OH)2D) was 1.8-times lower (P < 0.001). The gene and protein expression of enzymes, involved in the hydroxylation and renal uptake of vitamin D remained largely unaffected by the D-vitamer. In contrast to the mice data, hepatoma cells preferred vitamin D3 for 25-hydroxylation over vitamin D2 (P < 0.001). In general, the formation of 25(OH)D was much more pronounced in human than in murine hepatoma cells (P < 0.001). To conclude, in contrast to humans, vitamin D2 was more efficient in increasing 25(OH)D than vitamin D3 in mice, although this difference was not caused by a preferential hydroxylation of vitamin D2 in the liver. The metabolic routes of D3 and D2 in mice differ, showing lower circulating 1,25(OH)2D and tissue vitamin D concentrations in D2- than in D3-fed mice.

Enhancement in brain uptake of vitamin D3 nanoemulsion for treatment of cerebral ischemia: formulation, gamma scintigraphy and efficacy study in transient middle cerebral artery occlusion rat models.

AIM: For the treatment of cerebral ischaemia, vitamin-D3 loaded nanoemulsions were developed. METHOD: Tween 20 and polyethylene glycol were chosen as surfactant/co-surfactant, while oleic acid as the oil phase. The formulation was characterised for various in-vitro parameters. Targeting efficiency was investigated through radiometry, gamma scintigraphy and efficacy was studied in transient middle cerebral artery occlusion (MCAo) rat model. RESULT: Vitamin D3-nanoemulsion showed a mean size range of 49.29 ± 10.28 nm with polydispersity index 0.17 ± 0.04 and zeta potential 13.77 mV. The formulation was found stable during thermodynamic stability study and permeated within 180 min through sheep nasal mucosa (permeation coefficient 7.873 ± 0.884 cm/h). Gamma scintigraphy and radiometry assay confirmed better percentage deposition (2.53 ± 0.17%) of 99mTc-vitamin D3-nanoemulsion through nasal route compared to IV administered 99mTc-vitamin D3 solution (0.79 ± 0.03%). Magnetic Resonance Imaging (MRI) of the ischaemic model confirmed better efficacy of vitamin D3-nanoemulsion. CONCLUSION: This work demonstrated better permeation, deposition, and efficacy of vitaminD3-nanoemulsion through the intranasal route.

Encapsulation of vitamin D3 in gum arabic to enhance bioavailability and stability for beverage applications.

Delivery of vitamin D3 (VD3 ) in foods should exhibit desirable physicochemical characteristics and improves absorption. In this study, gum arabic (GA) was investigated as a VD3 carrier to encapsulate VD3 . VD3 dissolved in 5 mL ethanol corresponding to 0.3 to 6.0% mass of GA, was blended in 5.0% w/v GA solution, followed by freeze drying. The encapsulation efficiency decreased while loading capacity increased with an increased amount of VD3 . At the highest VD3 level, the loading capacity (3.47%) was the highest, and the encapsulation efficiency (61.24%) was satisfactory, and the treatment was further studied. The magnitude of negative zeta-potential increased from 3.1 to 31.0 mV at pH 2.0 to 7.4. During the 100-day storage at 3 °C of capsules reconstituted at pH 2.0 to 7.4, the hydrodynamic diameter decreased at all pH conditions, most evident for reduction to 81.3 nm at pH 7.4, and no precipitation was observed, indicating the significance of steric repulsion on capsule stability. Bioaccessibility of VD3 in capsules (95.76%) was significantly higher than the nonencapsulated VD3 (68.98%). The in vivo pharmacokinetic study in Sprague-Dawley rats after a single-dose of 300 µg VD3 showed the area-under-curve of serum 25(OHD) level in 48 hr of the encapsulation treatment was 4.32-fold of the nonencapsulated VD3 and more than twice higher than the VD3 -GA physical mixture. During 2-week supplementation of 60 µg VD3 /d, rats receiving capsules or physical mixture had 25(OH)D levels of at least 81 ng/mL higher than that of the nonencapsulated VD3 group. The studied encapsulation system holds great potential as a value-added ingredient to supplement VD3 in beverages with a wide pH range. PRACTICAL APPLICATION: The findings of this study demonstrated the improved dispersion stability and absorption of vitamin D3 after encapsulation in gum arabic. The capsules exhibited good dispersion stability across a pH range between 2.0 and 7.4, showing potential application in beverages. Furthermore, the enhanced absorption of VD3 after encapsulation highlights the nutritional benefits of the studied encapsulation system.

[Dynamics of indicators of vitamin D status in children with cystic fibrosis of the Moscow region for 2016-2018].

Vitamin D deficiency is widespread in patients with cystic fibrosis (CF). From 2016 to 2018, prophylactic doses of vitamin D were prescribed for the patients of the Russian cystic fibrosis Center in accordance with the National cystic fibrosis consensus and they were informed about the role of vitamin D deficiency. The aim of the study was to conduct a comparative analysis of the frequency of deficiency and insufficiency of vitamin D in children with CF of different ages in Moscow region in 2016 and 2018. Material and methods. The study involved 115 patients with CF at the age of 0-18 in 2016 and 211 children of the same age in 2018. All children underwent determination of 25(OH)D in blood serum by ELISA. Results and discussion. The frequency of vitamin D deficiency and insufficiency [25(OH)D level <30 ng/ml] in CF patients in 2016 was 64.3%, and in 2018 - 48.7%. Among children of 0-3 years normal serum 25(OH)D levels (>30 ng/ml) were registered in 62.5% in 2016 and in 62.2% in 2018, in children of 4-11 years - 28.8% in 2016 and 58.1% in 2018, among adolescents (11-18 years) - 11.8 and 30.2%, respectively. Conclusion. Comparative analysis showed a positive dynamics in reducing the proportion of CF patients with vitamin D deficiency and insufficiency against the background of continuous use of prophylactic doses of cholecalciferol and educational work for the period from 2016 to 2018. However, in a significant proportion of patients (48.7%), vitamin D level did not reach the norm in 2018 that requires the correction of preventive doses and increase in patient compliance.

Pharmacokinetics of Oral Cholecalciferol in Healthy Subjects with Vitamin D Deficiency: A Randomized Open-Label Study.

BACKGROUND: the aim of this study was to investigate the pharmacokinetic (PK) and safety profile of high-dose vitamin D supplementation, comparing different schedules (daily, weekly, or bi-weekly) in an otherwise healthy vitamin D-deficient population. Methods: single-center, open-label study on healthy subjects deficient in vitamin D (25 (OH)D < 20 ng/mL), randomized to receive cholecalciferol (DIBASE®, Abiogen Pharma, Italy) using three different schedules: Group A: 10,000 IU/day for eight weeks followed by 1000 IU/day for four weeks; Group B: 50,000 IU/week for 12 weeks, Group C: 100,000 IU/every other week for 12 weeks. Total cumulative doses were: 588,000 IU, 600,000 IU, 600,000 IU. The treatment regimens corresponded to the highest doses allowed for cholecalciferol for the correction of vitamin D deficiency in adults in Italy. RESULTS: mean 25 (OH)D plasma levels significantly increased from baseline 13.5 ± 3.7 ng/mL to peak values of 81.0 ± 15.0 ng/mL in Group A, 63.6 ± 7.9 ng/mL in Group B and 59.4 ± 12 ng/mL in Group C. On day 28, all subjects showed 25 (OH)D levels ≥ 20 ng/mL and 93.1% had 25 (OH)D levels ≥ 30 ng/mL. On day 56 and 84, all subjects had 25 (OH)D levels ≥ 30 ng/mL. No serious adverse events occurred during the study. CONCLUSIONS: normalization of 25 (OH)D serum levels was quickly attained with all the studied regimens. A more refracted schedule provided a higher systemic 25 (OH)D exposure.

Vitamin D Metabolism Is Dysregulated in Asthma and Chronic Obstructive Pulmonary Disease.

Rationale: Vitamin D deficiency is common in patients with asthma and chronic obstructive pulmonary disease (COPD). Low 25-hydroxyvitamin D (25[OH]D) levels may represent a cause or a consequence of these conditions.Objectives: To determine whether vitamin D metabolism is altered in asthma or COPD.Methods: We conducted a longitudinal study in 186 adults to determine whether the 25(OH)D response to six oral doses of 3 mg vitamin D3, administered over 1 year, differed between those with asthma or COPD versus control subjects. Serum concentrations of vitamin D3, 25(OH)D3, and 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) were determined presupplementation and postsupplementation in 93 adults with asthma, COPD, or neither condition, and metabolite-to-parent compound molar ratios were compared between groups to estimate hydroxylase activity. Additionally, we analyzed 14 datasets to compare expression of 1α,25(OH)2D3-inducible gene expression signatures in clinical samples taken from adults with asthma or COPD versus control subjects.Measurements and Main Results: The mean postsupplementation 25(OH)D increase in participants with asthma (20.9 nmol/L) and COPD (21.5 nmol/L) was lower than in control subjects (39.8 nmol/L; P = 0.001). Compared with control subjects, patients with asthma and COPD had lower molar ratios of 25(OH)D3-to-vitamin D3 and higher molar ratios of 1α,25(OH)2D3-to-25(OH)D3 both presupplementation and postsupplementation (P ≤ 0.005). Intergroup differences in 1α,25(OH)2D3-inducible gene expression signatures were modest and variable if statistically significant.Conclusions: Attenuation of the 25(OH)D response to vitamin D supplementation in asthma and COPD associated with reduced molar ratios of 25(OH)D3-to-vitamin D3 and increased molar ratios of 1α,25(OH)2D3-to-25(OH)D3 in serum, suggesting that vitamin D metabolism is dysregulated in these conditions.

Transdermal vitamin D supplementation-A potential vitamin D deficiency treatment.

Vitamin D deficiency has high prevalence worldwide. Vitamin D3, the active form of vitamin D, exhibits array of roles in body, from calcium homeostasis and bone mineralization to cancer, neurological disorders, immunomodulatory action, and cardiac health. Current approaches for supplementing vitamin D3 are restricted to oral and parenteral routes. This review highlights recent research in the field of transdermal delivery of vitamin D, its active form and analogues with the aid of penetration enhancers and novel carrier system as nutritional supplement in case of vitamin D deficiency. The penetration of vitamin D3 is challenging; however, by means of reducing hydrophobicity of the active and encapsulating vitamin D3 in a suitable carrier system, penetration is achieved. The results show that penetration of vitamin D3 through skin is feasible. Further clinical trials could strengthen these results. However, the present research till date shows transdermal vitamin D3 a promising way of supplementation.

Stability and bioavailability of vitamin D3 encapsulated in composite gels of whey protein isolate and lotus root amylopectin.

A gel delivery system was developed in the present work using whey protein isolate and lotus root amylopectin via regulating pH. The texture, thermodynamics, rheology and microstructure of gels were evaluated. Results showed that pH at 7.0 induced a more compact and stable gel structure than other pH. The composite gel formed at pH 7.0 was accordingly employed to encapsulate vitamin D3. Results exhibited that the encapsulation of composite gel of whey protein isolate and lotus root amylopectin could enhance the storage stability of vitamin D3 and protect vitamin D3 from photochemical degradation. Moreover, this encapsulation could control the release of vitamin D3 in simulated intestinal fluid. Animal experiments exhibited that the bioavailability was significantly increased after vitamin D3 was encapsulated by the composite gel. This work indicated that the whey protein isolate-lotus root amylopectin gel is a good delivery system to improve the stability and bioavailability of vitamin D3.

Intake of ergosterol increases the vitamin D concentrations in serum and liver of mice.

Factors that can modify the bioavailability of orally administered vitamin D are not yet widely known. Ergosterol is a common fungal sterol found in food which has a chemical structure comparable to that of vitamin D. This study aimed to investigate the effect of ergosterol on vitamin D metabolism. Therefore, 36 male wild type-mice were randomly subdivided into three groups (n = 12) and received a diet containing 25 µg vitamin D3 and either 0 mg (control), 2 mg or 7 mg ergosterol per kg diet for 6 weeks. To elucidate the impact of ergosterol on hepatic hydroxylation of vitamin D, human hepatoma cells (HepG2) were treated with different concentrations of ergosterol. Concentrations of vitamin D3 and 25-hydroxyvitamin D3 (25(OH)D3) in cells, livers and kidneys of mice and additionally 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in serum were quantified by LC-MS/MS. The concentration of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in serum was analyzed by commercially-available enzyme immuno assay. The concentrations of cholesterol and triglycerides were analyzed in livers of mice by photometric assays. Analyses revealed that mice receiving 7 mg/kg ergosterol with their diet had 1.3-, 1.7- and 1.5-times higher concentrations of vitamin D3 in serum, liver and kidney, respectively, than control mice (P < 0.05), whereas no significant effects were observed in mice fed 2 mg/kg ergosterol. The hydroxylation of vitamin D remained unaffected by dietary ergosterol, since the concentration of 25-hydroxyvitamin D3 in serum and tissues and the concentrations of 1,25(OH)2D3 and 24,25(OH)2D3 in serum were not different between the three groups of mice. The lipid concentrations in liver were also not affected by dietary ergosterol. Data from the cell culture studies showed that ergosterol did not influence the conversion of vitamin D3 to 25(OH)D3. To conclude, ergosterol appears to be a modulator of vitamin D3 concentrations in the body of mice, without modulating the hydroxylation of vitamin D3 in liver.

Impact of an indigestible oil phase (mineral oil) on the bioaccessibility of vitamin D3 encapsulated in whey protein-stabilized nanoemulsions.

These is some interest in replacing digestible fats with indigestible ones to decrease the energy-density of foods. The utilization of indigestible oils, however, may have unforeseen nutritional consequences, such as the reduction of vitamin bioavailability. In this study, the impact of an indigestible oil on the bioaccessibility of emulsified vitamin D3 (VD) was examined. We prepared four kinds of nanoemulsions using different combinations of a digestible oil (DO) and an indigestible oil (IO): DO only; IO only; an oil mixture (OM) consisting of 1:1 DO:IO mixed before homogenization; and, an emulsion mixture (EM) consisting of 1:1 DO:IO nanoemulsions mixed after homogenization. A gastrointestinal tract (GIT) model was employed to elucidate the kinetics of VD bioaccessibility from the nanoemulsions. Both the lipid digestion rate and vitamin bioaccessibility decreased in the same order: DO > OM ≈ EM > IO. The change in vitamin bioaccessibility over time under simulated small intestine conditions was also measured. With the exception of the IO nanoemulsions, the vitamin bioaccessibility increased to a maximum value after around 30 min, but then decreased during the following 24 h. This effect was attributed to an initial solubilization of the vitamin within the mixed micelles, followed by their precipitation during prolonged incubation. Our results show that lipid digestion, micelle solubilization, and micelle aggregation impact the in vitro bioaccessibility of vitamin D. This knowledge may be helpful for designing more efficacious nanoemulsion-based delivery systems for fat-soluble vitamins.

Obesity attenuates serum 25-hydroxyvitamin D response to cholecalciferol therapy in critically ill patients.

OBJECTIVES: The presence of obesity may confound cholecalciferol dosing in vitamin D-deficient patients owing to potentially decreased bioavailability. The aim of this retrospective study was to evaluate cholecalciferol therapy in vitamin D-deficient, critically ill trauma patients with and without obesity. METHODS: Adult patients with severe traumatic injuries who had a serum 25-hydroxyvitamin D (25-OH vit D) <50nmol/L were prescribed 10 000 IU of liquid cholecalciferol daily. Efficacy was defined as achievement of a 25-OH vit D of 75 to 200nmol/L. Safety was evaluated by the presence of hypercalcemia (serum ionized calcium >1.32 mmol/L). Fifty-three patients (18 obese, 35 non-obese) were identified for study. RESULTS: Despite similar baseline concentrations (36 ± 7 versus 37 ± 7 nmol/L; P = NS), 25-OH vit D response was attenuated for those with obesity after 1 and 2 wk of cholecalciferol therapy (51 ± 18 versus 66 ± 27nmol/L, P < 0.01; 68 ± 19 versus 92 ± 25nmol/L, P < 0.01, respectively). Patients with obesity also tended to experience less hypercalcemia (22% versus 49% of patients, respectively) post-cholecalciferol therapy. CONCLUSION: Obesity alters the response to cholecalciferol therapy in critically ill patients with severe traumatic injuries.