Pharmacokinetics of vitamin D toxicity

Abstract

Although researchers first identified the fat-soluble vitamin cholecalciferol almost a century ago and studies have now largely elucidated the transcriptional mechanism of action of its hormonal form, 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], we know surprisingly little about mechanisms of vitamin D toxicity. The lipophilic nature of vitamin D explains its adipose tissue distribution and its slow turnover in the body (half-life approximately 2 mo). Its main transported metabolite, 25-hydroxyvitamin D(3) [25(OH)D(3)], shows a half-life of approximately 15 d and circulates at a concentration of 25-200 nmol/L, whereas the hormone 1alpha,25(OH)(2)D(3) has a half-life of approximately 15 h. Animal experiments involving vitamin D(3) intoxication have established that 25(OH)D(3) can reach concentrations up to 2.5 mumol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO(4) product. The rise in 25(OH)D(3) is accompanied by elevations of its precursor, vitamin D(3), as well as by rises in many of its dihydroxy- metabolites [24,25(OH)(2)D(3); 25,26(OH)(2)D(3); and 25(OH)D(3)-26,23-lactone] but not 1alpha,25(OH)(2)D(3). Early assumptions that 1alpha,25(OH)(2)D(3) might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D(3) at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1alpha,25(OH)(2)D from vitamin D binding, increasing its free concentration and thus increasing gene transcription. Occasional anecdotal reports from humans intoxicated with vitamin D appear to support the latter mechanism. Although current data support the viewpoint that the biomarker plasma 25(OH)D concentration must rise above 750 nmol/L to produce vitamin D toxicity, the more prudent upper limit of 250 nmol/L might be retained to ensure a wide safety margin.

Vitamin D supplementation differentially affects seasonal multiple sclerosis disease activity

“…Therefore, UVB radiation of late summer might also influence relapses in the fourth quarter of the year. The approximately 15-day half-life of 25(OH)D 3 might play a key role in this lag (Jones, 2008). As our work was a purely retrospective study of medical records, we cannot provide seasonal immunological data to support our explanation for the lag in relapse rates.…”

“…The relapse peak was recorded in early spring (March) and the relapse trough in autumn (October), which indicate an annual cyclical pattern of MS disease activity (Spelman et al, 2014). As UVB radiation is lowest during the winter months (Webb et al, 1988) and 25(OH)D 3 has a half-life of approximately 15 days (Jones, 2008), VD deficiency increases during winter. Consequently, hypovitaminosis D has the most substantial impact on the immune system in late winter/early spring.…”

Vitamin D Deficiency and Its Association with Thyroid Disease

“…It reflects vitamin D produced cutaneously and that obtained from food and supplements (18) and has a fairly long circulating half-life of 15 days. (19) In contrast to 25(OH)D, circulating 1,25(OH) 2 D is generally not a good indicator of vitamin D status because it has a short half-life of 15 hours and serum concentrations are closely regulated by parathyroid hormone, calcium, and phosphate (19) . Levels of 1, 25(OH) 2 D do not typically decrease until vitamin D deficiency is severe.…”

Oral vitamin D supplementation has a lower bioavailability and reduces hypersecretion of parathyroid hormone and insulin resistance in obese Chinese males

“…Since vitamin D nutritional status may be important in regulating obesity (3)(4)(5)(6) , interest was aroused to study Chinese obese males in this regard. Circulating 25-hydroxyvitamin D (25(OH)D; calcidiol), a metabolite of vitamin D having a half-life of 2-3 weeks, is recommended as a reliable marker of vitamin D nutritional status (7)(8)(9)(10) . The US Institute of Medicine (11) reports that a circulating 25(OH)D concentration equal to 50 nmol/l (20 ng/ml) meets the vitamin D requirements of 97·5 % of the population, and this threshold is widely accepted for hypovitaminosis D (10,(12)(13)(14) .…”