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

背景资料：维生素D3，也称为胆钙化醇，是一种精油可溶的开环甾类激素，由皮肤中的7-脱氢胆固醇通过紫外线B（UVB; 219-315 nm）合成，并由肝脏和肾脏代谢成其活性形式。胆钙化醇也可以从食物中获得，但由于阳光照射不足和饮食摄入量有限，据报道全球约有10亿人缺乏维生素D（McCourt等人，Nutrition，75-76，110767）。维生素D补充剂的世界范围销售正在增加，但是这些补充剂中的绝大多数是口服给药的。口服维生素D补充剂存在依从性差、胃肠道（GI）副作用、过量的风险和质量差的问题（Boonen等人，2006. J Intern Med，259：539-52; Unson等人，2006.当代临床试验，27，215-26，Wan等人，14521），因此需要提供补充维生素D的替代方法。初步研究：胆钙化醇在口服吸收后是化学不稳定的，但它可以在人皮肤的表皮中直接代谢成其更化学稳定的活性形式1a，25（OH）2D 3，因此通过皮肤递送这种维生素是有吸引力的（Lehman等人，Exp Dermatol 2000：9：97-103）。然而，胆钙化醇是非常亲脂的（计算的Log P为6.58，MarvinSketch），并且当应用于皮肤表面时，它不会进入表皮，因为它保留在皮肤的死细胞外层角质层中（Taylor和Davies，2018 Br.临床药学杂志，84：1121-1127）。假设：使用热贴片对皮肤进行轻度热疗可用于增强局部皮肤对维生素D的代谢和吸收，从而促进这种维生素的有效给药方式。项目将：1.）了解轻度皮肤热疗（最高50摄氏度，在商业疼痛热贴中显示是安全的）如何影响皮肤中局部胆钙化醇和新型King合成的前胆钙化醇D代谢。确定使用Curapel贴剂产生的轻度高热的速率和程度（长达6小时）如何影响皮肤中维生素D的吸收和生物分布。3.）第三章在体内确定轻度皮肤高温诱导的血流变化如何改变直接皮肤递送后的维生素D代谢、吸收和药代动力学。

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.