Abstract
Vitamin D(3)'s role in mineral homeostasis through its endocrine function, associated with the main circulating metabolite 25-hydroxyvitamin D(3), is well characterized. However, the increasing recognition of vitamin D(3)'s paracrine and autocrine functions-such as cell growth, immune function, and hormone regulation-necessitates examining vitamin D(3) levels across different tissues post-supplementation. Hence, this review explores the biodistribution of vitamin D(3) in blood and key tissues following oral supplementation in humans and animal models, highlighting the biologically active metabolite, 1,25-dihydroxyvitamin D(3), and the primary clearance metabolite, 24,25-dihydroxyvitamin D(3). 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 D(3) needs and metabolic alterations, where data remains sparse. Within the examined dosage ranges, both human and animal studies indicate that vitamin D(3) and its metabolites are retained in tissues selectively. Notably, vitamin D(3) 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 D(3) levels may not adequately reflect vitamin D(3) and its metabolite concentrations in different tissues. Therefore, future research should aim to generate robust human data on the tissue distribution of vitamin D(3) and its principal metabolites post-supplementation. Relating this data to clinically appropriate exposure metrics will enhance our understanding of vitamin D(3)'s cellular effects and guide refinement of clinical trial methodologies.