Supplemental 25-Hydroxycholecalciferol Is More Effective than Cholecalciferol in Raising Serum 25-Hydroxyvitamin D Concentrations in Older Adults.

BACKGROUND: There are few studies directly comparing the pharmacokinetics of 25-hydroxycholecalciferol [25(OH)D3] to cholecalciferol (D3). OBJECTIVES: The primary objectives were to compare the effectiveness of D3 and 25(OH)D3 in raising 25-hydroxyvitamin D [25(OH)D] serum concentrations and achieving steady state. METHODS: This was a randomized, double-blind, active comparator trial of 91 participants (53 females, 38 males), aged 63.3 ± 7.9 y. 25(OH)D3 (10, 15, and 20 µg) and D3 (20 µg) were dosed daily for 6 mo followed by 6 mo of washout. Frequent measurements of serum 25(OH)D were performed. Pharmacokinetic parameters were fitted for each individual and the treatment average was modeled with linear regression using the individual baseline level, sex, and gender as covariates. RESULTS: Mean baseline 25(OH)D was similar in all groups (47.1-49.5 nmol/L). Increases in 25(OH)D to steady state were higher in the 25(OH)D3 groups than in the D3 group [least squares (LS) means (95% CI): 50.1 (43.3-58.0), 72.5 (64.3-81.7), 97.4 (86.6-109.6) nmol/L in 10, 15, and 20 µg/d and 38.7 (33.1-45.2) nmol/L in the D3 group; P = 0.0173, P < 0.0001, P < 0.0001]. The rate to reach steady state was similar in all groups, but the time to reach 25(OH)D concentrations of 75 nmol/L was faster in the higher-dosed 25(OH)D3 groups than in the D3 group (7 and 10 d compared with 40 d, P < 0.0001 and P < 0.0001 for 15 and 20 µg/d). The rate of elimination was 59-109% higher in the 25(OH)D3 groups than in the D3 group. The area under the curve (AUC)/µg dose demonstrated that 25(OH)D3 was 3 times as effective as D3 at raising 25(OH)D concentrations. CONCLUSIONS: 25(OH)D3 is ∼3 times as effective as D3 at raising 25(OH)D concentrations. Once supplementation is discontinued, the elimination rate of 25(OH)D3 is faster than D3. This trial was registered at clinicaltrials.gov as NCT02333682.

Effects of formulation on the bioavailability of lutein and zeaxanthin: a randomized, double-blind, cross-over, comparative, single-dose study in healthy subjects.

PURPOSE: Lutein and zeaxanthin are macular pigments with a protective function in the retina. These xanthophylls must be obtained from the diet or added to foods or supplements via easy-to-use, stable formulations. The technique employed to produce these formulations may affect the bioavailability of the xanthophylls. METHODS: Forty-eight healthy volunteers were randomized into this double-blind, cross-over study investigating the plasma kinetics of lutein provided as two different beadlet formulations. Subjects (n = 48) received a single dose of 20 mg of lutein as either a starch-matrix ("SMB", FloraGLO® Lutein 5 %) or as a cross-linked alginate-matrix beadlet ("AMB", Lyc-O-Lutein 20 %) formulation. Plasma concentrations of lutein and zeaxanthin were measured at 0, 1, 3, 6, 9, 12, 14, 24, 26, 28, 32, 36, 48, 72, 168, and 672 h. RESULTS: The mean plasma AUC(0-72h), AUC(0-672h), and C(max) for total lutein and zeaxanthin and their all-E-isomers were significantly increased (p < 0.001) from pre-dose concentrations in response to SMB and AMB. There was no difference in lutein T max between the two test articles. However, by 14 h post-dose, total plasma lutein increased by 7 % with AMB and by 126 % with SMB. Total lutein AUC(0-72h) and AUC(0-672h) were 1.8-fold and 1.3-fold higher, respectively, for SMB compared to AMB. Both formulations were well tolerated by subjects in this study. CONCLUSION: These findings confirm that the bioavailability of lutein and zeaxanthin critically depends on the formulation used and document a superiority of the starch-based over the alginate-based product in this study.

Drug interaction potential of resveratrol.

Resveratrol is a naturally occurring polyphenol that is often used as a food supplement. Many positive health effects, including cardio protection, tumor suppression, and immune modulation, are associated with the intake of resveratrol. Resveratrol is well tolerated in healthy subjects without any comedication. However, supplemental doses of resveratrol in the range of 1 g/day or above by far exceed the natural intake through food. Whether resveratrol-drug interactions can be harmful in patients taking additional medications remains unknown. Recent in vivo studies and clinical trials indicate a possible drug-drug interaction potential using high-dosage formulations. In this review, the known in vitro and in vivo effects of resveratrol on various cytochrome P450 (CYP) isoenzymes are summarized. They are discussed in relation to clinically relevant plasma concentrations in humans. We conclude that resveratrol may lead to interactions with various CYPs, especially when taken in high doses. Aside from systemic CYP inhibition, intestinal interactions must also be considered. They can potentially lead to reduced first-pass metabolism, resulting in higher systemic exposure to certain coadministrated CYP substrates. Therefore, patients who ingest high doses of this food supplement combined with additional medications may be at risk of experiencing clinically relevant drug-drug interactions.

Safety studies conducted on high-purity trans-resveratrol in experimental animals.

trans-Resveratrol is a naturally occurring polyphenolic compound found in a variety of foods, but predominantly in grapes. Safety studies were conducted on high-purity trans-resveratrol (Resvida), including skin and eye irritation, dermal sensitization, subchronic and reproductive toxicity, genotoxicity, and absorption, metabolism and excretion. Resvida was non-irritating to skin and eyes and non-sensitizing. It was non-mutagenic in a bacterial reverse mutation assay in Salmonella typhimurium and Escherichia coli, but exhibited clastogenic activity in a chromosomal aberration test in human lymphocytes. However, in an in vivo bone marrow micronucleus test in rats, Resvida was non-genotoxic. In a 28-day study, Resvida caused no adverse effects in rats at 50, 150 and 500 mg/kg bw/day. Similarly, in a 90-day study, Resvida did not cause any adverse effects in rats at up to 700 mg/kg bw/day; the highest dose tested. Resvida did not induce any adverse reproductive effects in an embryo-fetal toxicity study in rats at a dose of 750 mg/kg bw/day. Also, in vitro and in vivo absorption, metabolism, and excretion studies in Caco-2 cells, rat primary hepatocytes and male and female rats (in vivo) show that Resvida is readily absorbed, metabolized and excreted. These studies provide evidence that Resvida is well tolerated and non-toxic.

The role of Glu181 in the photoactivation of rhodopsin.

The visual pigment rhodopsin is a prototypical seven transmembrane helical G protein-coupled receptor. Photoisomerization of its protonated Schiff base (PSB) retinylidene chromophore initiates a progression of metastable intermediates. We studied the structural dynamics of receptor activation by FTIR spectroscopy of recombinant pigments. Formation of the active state, Meta II, is characterized by neutralization of the PSB and its counterion Glu113. We focused on testing the hypothesis of a PSB counterion switch from Glu113 to Glu181 during the transition of rhodopsin to the still inactive Meta I photointermediate. Our results, especially from studies of the E181Q mutant, support the view that both Glu113 and Glu181 are deprotonated, forming a complex counterion to the PSB in rhodopsin, and that the function of the primary counterion shifts from Glu113 to Glu181 during the transition to Meta I. The Meta I conformation in the E181Q mutant is less constrained compared with that of wild-type Meta I. In particular, the hydrogen bonded network linking transmembrane helices 1, 2, and 7, adopts a conformation that is already Meta II-like, while other parts of the receptor appear to be in a Meta I-like conformation similar to wild-type. We conclude that Glu181 is responsible, in part, for controlling the extraordinary high pK(a) of the chromophore PSB in the dark state, which very likely decreases upon transition to Meta I in a stepwise weakening of the interaction between PSB and its complex counterion during the course of receptor activation. A model for the specific role in coupling chromophore isomerization to protein conformational changes concomitant with receptor activation is presented.