Understanding how mild skin hyperthermia influences vitamin D skin absorption and metabolism during nutritional supplementation

Background: Vitamin D3, also known as cholecalciferol, is an essential oil-soluble secosteroid hormone synthesised from 7-dehydrocholesterol in the skin by ultraviolet B (UVB; 219-315 nm) and metabolised by the liver and kidney into its active form. Cholecalciferol can also be obtained from foods, but due to insufficient sun exposure and limited dietary intake approximately 1 billion people reported to be vitamin D deficient globally (McCourt et al., Nutrition, 75-76, 110767).
The world-wide sales of vitamin D supplements are increasing but, the vast majority of these supplements are orally administered. The oral vitamin D supplements suffer from poor compliance, gastrointestinal (GI) side-effects, the risk of overdose and poor quality (Boonen et al., 2006. J Intern Med, 259:539-52; Unson et al., 2006. Contemporary clinical trials, 27, 215-26, Wan et al., 2020 in press https://doi.org/10.1111/bcp.14521), therefore there is a need to provide alternative methods of vitamin D supplementation.
Preliminary Research: Cholecalciferol is chemically unstable after oral absorption, but it can be directly metabolised to its more chemically stable active form 1a,25(OH)2D3 in the epidermis of human skin thus delivery of this vitamin via the skin is attractive (Lehman et al., Exp Dermatol 2000: 9: 97-103). However, cholecalciferol is very lipophilic (calculated Log P is 6.58, MarvinSketch) and when applied to the surface of the skin it does not pass into the epidermis because it is retained in the skin's outer lipidic layer of dead cells, the Stratum corneum (Taylor and Davies, 2018 Br. J. Clin. Pharm., 84:1121-1127).
Hypothesis: The application of mild hyperthermia to the skin using a thermal patch can be used to enhance the local skin metabolism and absorption of vitamin D, thus facilitating an effective means to administer this vitamin.
Objectives: The Ph.D. project will: 1.) Understand how mild skin hyperthermia (Maximum of 50 degrees C, shown to be safe in commercial pain heat patches) influences local cholecalciferol and novel King's synthesised pre-cholecalciferol D metabolism in the skin 2.) Determine how the rate and extent (up to 6 h) of mild hyperthermia generated using the Curapel patch influences vitamin D absorption and biodistribution in the skin. 3.) Determine, in vivo, how the mild skin hyperthermia induced blood flow changes modify vitamin D metabolism, absorption and pharmacokinetics after direct skin delivery.