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A physiologically based pharmacokinetic model of vitamin D
Citation:
Sawyer, M., H. Tran, AND M. Evans. A physiologically based pharmacokinetic model of vitamin D. JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 37(12):1448-1454, (2017).
Impact/Purpose:
This study presents an application of PBPK modeling to describe the formation of Vitamin D3. Recently, there has been a surge of interest in the health benefits of Vitamin D3, from heart health to cancer. Despite its importance, a PBPK model for Vitamin D3 does not exist in the literature. Due to its anti-inflammatory properties, Vitamin D3 is being prescribed to patients suffering diverse chronic illnesses. Because of its importance in several conditions, we thought it was important to understand its metabolic formation from precursors and distribution in the body. Time course data from the literature following the effect of oral supplementation in healthy adults was used to develop the first PBPK model for Vitamin D formation. The goal of this paper was to develop a PBPK model describing the metabolic formation of Vitamin D (as Vitamin D3) when receiving oral supplementation. In the process of developing the PBPK model, several novel concepts were used. For example, due to the extreme lipophilic nature of this vitamin (derived from cholesterol), partition coefficients were varied as a function of dose and time. Also, the regulation of enzymatic metabolism by its product (Vitamin D) was also examined. The result was a very different approach used, and a PBPK model that describes an essential vitamin in the body. The Agency is interested in development of PBPK models that apply to many chemicals or specific populations that might be more sensitive to exposure. We are currently faced with an increase in Vitamin D3 deficiency in the general population and a concurrent increase in certain chronic illnesses. Since Vitamin D appears to be important as an anti-inflammatory agent for multiple chronic diseases, and oral supplementation is being used in clinical subpopulations to help fight chronic illnesses, the development of this PBPK model helps with the overall effort of understanding the final pathways involved in Vitamin D formation. These pathways may be altered with disease, and the current model can serve as a building block for supplemented population that are exposed to environmental contaminants.
Description:
Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 μg and 10 μg) supplementation of vitamin D over the course of 28 days in the absence of sunlight. Vitamin D and its metabolites are highly lipophilic and binding assays of these compounds in serum may not account for binding by lipids and additional proteins. To compensate for the additional bound amounts, this study allowed the effective adipose–plasma partition coefficient to vary dynamically with the concentration of each compound in serum utilizing the Hill equation for binding. Through incorporating the optimized parameters with the adipose partition coefficient adaptation to the PBPK model, this study was able to fit serum concentration data for circulating vitamin D at all three supplementation concentrations within confidence intervals of the data
