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

了解营养补充过程中轻度皮肤热疗如何影响维生素 D 皮肤吸收和代谢

• 批准号: 2548636
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2548636
• 关键词: Understanding; how; mild; skin; hyperthermia

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.

背景：维生素D3，也称为胆钙化醇，是一种精油溶性类固醇激素，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取，但由于阳光照射不足和饮食摄入有限，据报告全球约有 10 亿人缺乏维生素 D（McCourt 等人，营养学，75-76, 110767）。全球维生素 D 补充剂的销量正在增加，但绝大多数这些补充剂都是口服给药。口服维生素 D 补充剂存在依从性差、胃肠道 (GI) 副作用、过量风险和质量差等问题（Boonen 等人，2006 年。 J Intern Med，259：539-52；Unson 等人，2006 年。当代临床试验，27, 215-26，Wan 等人，2020 年出版中） https://doi.org/10.1111/bcp.14521），因此需要提供补充维生素D的替代方法。初步研究：胆钙化醇口服吸收后化学性质不稳定，但它可以在人体皮肤表皮中直接代谢为其化学性质更稳定的活性形式1a,25(OH)2D3，从而输送这种物质 通过皮肤摄入维生素是有吸引力的(Lehman等人，Exp Dermatol 2000：9：97-103)。然而，胆钙化醇具有很强的亲脂性（计算得出的 Log P 为 6.58，MarvinSketch），当应用于皮肤表面时，它不会进入表皮，因为它保留在皮肤死细胞的外部脂质层中，即角质层中（Taylor 和 Davies，2018 Br. J. Clin. Pharm.， 84:1121-1127). 假设：温和的应用 使用热贴对皮肤进行热疗可增强局部皮肤的新陈代谢和维生素 D 的吸收，从而促进维生素 D 的有效施用。项目将： 1.) 了解温和的皮肤热疗（最高 50 摄氏度，在商业疼痛热贴中被证明是安全的）如何影响局部胆钙化醇和新型 King 合成的前胆钙化醇 D 在皮肤中的代谢 2.) 确定使用 Curapel 贴片产生的温和热疗的速率和程度（最多 6 小时）如何影响皮肤中维生素 D 的吸收和生物分布。 3.) 在体内确定直接皮肤递送后温和的皮肤热疗引起的血流变化如何改变维生素 D 的代谢、吸收和药代动力学。