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Pharmacokinetics of vitamin D toxicity^1,2,3,4

¹ From the Departments of Biochemistry and Medicine, Queen's University, Kingston, Ontario, Canada

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, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], 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 2 mo). Its main transported metabolite, 25-hydroxyvitamin D₃ [25(OH)D₃], shows a half-life of 15 d and circulates at a concentration of 25–200 nmol/L, whereas the hormone 1,25(OH)₂D₃ has a half-life of 15 h. Animal experiments involving vitamin D₃ intoxication have established that 25(OH)D₃ can reach concentrations up to 2.5 µmol/L, at which it is accompanied by hypercalcemia and other pathological sequelae resulting from a high Ca/PO₄ product. The rise in 25(OH)D₃ is accompanied by elevations of its precursor, vitamin D₃, as well as by rises in many of its dihydroxy- metabolites [24,25(OH)₂D₃; 25,26(OH)₂D₃; and 25(OH)D₃-26,23-lactone] but not 1,25(OH)₂D₃. Early assumptions that 1,25(OH)₂D₃ might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D₃ at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1,25(OH)₂D 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.

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