Vitamin D beyond the blood: Tissue distribution of vitamin D metabolites after supplementation

Vitamin D₃'s role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D₃, is well characterized. However, the increasing recognition of vitamin D₃'s paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D₃ levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D₃ in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D₃, and the primary clearance metabolite, 24,25-dihydroxyvitamin D₃. While our findings indicate significant progress in understanding how circulating metabolite levels respond to supplementation, comprehensive insight into their tissue concentrations remains limited. The gap is particularly significant during pregnancy, a period of drastically increased vitamin D₃ needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D₃ and its metabolites are retained in tissues selectively. Notably, vitamin D₃ concentrations in tissues show greater variability in response to administered doses. In contrast, its metabolites maintain a more consistent concentration range, albeit different among tissues, reflecting their tighter regulatory mechanisms following supplementation. These observations suggest that serum 25-hydroxyvitamin D₃ levels may not adequately reflect vitamin D₃ and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D₃ and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D₃'s cellular effects and guide refinement of clinical trial methodologies.