{"title":"利用药代动力学模型优化口服3-羟基丁酸酯剂量以改善健康受试者的认知功能和情绪。","authors":"Kentaro Nishioka, Takahiro Ishimoto, Mariko Sato, Ruki Yasuda, Yumi Nakamura, Hiroshi Watanabe, Toshihide Suzuki, Yudai Araragi, Yukio Kato, Ken-Ichi Yoshida, Norihito Murayama","doi":"10.3389/fnut.2024.1470331","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>The brain uses ketones, mainly 3-hydroxybutyrate (3-HB), as an alternative energy source. Therefore, oral intake of 3-HB may help maintain brain health. Previous studies indicated that achieving a maximum concentration (C<sub>max</sub>) of 3-HB in plasma at 0.28 mM could initiate ketone metabolism in the brain; we hypothesized that attaining this C<sub>max</sub> would improve brain health.</p><p><strong>Methods: </strong>We aimed to demonstrate the efficacy of an optimized single oral dose of 3-HB on cognitive function and mood through two clinical studies: a pharmacokinetic study and an efficacy study. In the pharmacokinetic study, healthy subjects were ingested 2 and 4 g of 3-HB to construct a compartment model to predict the minimum oral dose of 3-HB needed to achieve the target C<sub>max</sub>. In the efficacy study, a randomized, double-blinded, and placebo-controlled crossover trial, the effects of 3-HB at the predicted doses on cognitive function and mood in healthy subjects were assessed by a serial arithmetic test (SAT), the cognitrax, the profile of mood states 2nd edition (POMS2), and fatigue visual analog scale (VAS).</p><p><strong>Results: </strong>In the pharmacokinetic study, a one-compartment model that includes saturable and non-saturable absorption pathways, constant biosynthesis, and the linear elimination of 3-HB after oral administration were constructed. The model principally reflected the observed serum 3-HB concentrations profiles and predicted a minimum dose of 3.5 g needed to achieve the target C<sub>max</sub>. In the efficacy study, although no significant difference was observed in any cognitive domains assessed by the Cognitrax, total responses and correct answers in the SAT were significantly improved in the active group receiving 3.5 g of 3-HB compared to the placebo group. Regarding the POMS2, confusion-bewilderment, fatigue-inertia, vigor-activity, and total mood disturbance scales were significantly improved in the active group compared to the placebo group. Additionally, fatigue VAS were also significantly improved in the active group compared to the placebo group.</p><p><strong>Discussion: </strong>We successfully established a one-compartment model for oral 3-HB intake and demonstrated partial efficacy on cognitive function and broad efficacy on mood in healthy subjects with a single oral dose of 3.5 g of 3-HB optimized by the model.</p><p><strong>Clinical trial registration: </strong>https://www.umin.ac.jp/ctr/index-j.htm, identifier [UMIN000042095, UMIN000046666].</p>","PeriodicalId":12473,"journal":{"name":"Frontiers in Nutrition","volume":"11 ","pages":"1470331"},"PeriodicalIF":4.0000,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758625/pdf/","citationCount":"0","resultStr":"{\"title\":\"Optimizing oral 3-hydroxybutyrate dosage using pharmacokinetic model to improve cognitive function and mood in healthy subjects.\",\"authors\":\"Kentaro Nishioka, Takahiro Ishimoto, Mariko Sato, Ruki Yasuda, Yumi Nakamura, Hiroshi Watanabe, Toshihide Suzuki, Yudai Araragi, Yukio Kato, Ken-Ichi Yoshida, Norihito Murayama\",\"doi\":\"10.3389/fnut.2024.1470331\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>The brain uses ketones, mainly 3-hydroxybutyrate (3-HB), as an alternative energy source. 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引用次数: 0
摘要
大脑使用酮类，主要是3-羟基丁酸盐（3-HB）作为替代能源。因此，口服3-HB可能有助于维持大脑健康。先前的研究表明，达到血浆中3-HB的最大浓度（Cmax）为0.28 mM时，可启动脑内酮代谢；我们假设达到这个Cmax会改善大脑健康。方法：我们旨在通过两项临床研究：药代动力学研究和疗效研究，证明优化单次口服3-HB对认知功能和情绪的疗效。在药代动力学研究中，健康受试者分别摄取2和4 g的3-HB，构建室室模型，预测达到目标Cmax所需的最小口服3-HB剂量。疗效研究是一项随机、双盲、安慰剂对照的交叉试验，通过一系列算术测试（SAT）、认知量表（cognitrax）、情绪状态量表第二版（POMS2）和疲劳视觉模拟量表（VAS）评估预测剂量下3-HB对健康受试者认知功能和情绪的影响。结果：在药代动力学研究中，构建了一个单室模型，包括饱和和非饱和吸收途径、恒定的生物合成和口服给药后3-HB的线性消除。该模型主要反映了观察到的血清3-HB浓度分布，并预测达到目标Cmax所需的最小剂量为3.5 g。在疗效研究中，虽然在Cognitrax评估的任何认知领域没有观察到显着差异，但与安慰剂组相比，接受3.5 g 3-HB的活性组的SAT总反应和正确答案显着改善。关于POMS2，与安慰剂组相比，活跃组的困惑-困惑、疲劳-惯性、活力-活动和总情绪障碍量表显著改善。此外，与安慰剂组相比，活动组的疲劳VAS也有显著改善。讨论：我们成功建立了口服3-HB单室模型，经模型优化后，单次口服3.5 g的3-HB对健康受试者的认知功能有部分疗效，对情绪有广泛疗效。临床试验注册：https://www.umin.ac.jp/ctr/index-j.htm，标识符[UMIN000042095， UMIN000046666]。
Optimizing oral 3-hydroxybutyrate dosage using pharmacokinetic model to improve cognitive function and mood in healthy subjects.
Introduction: The brain uses ketones, mainly 3-hydroxybutyrate (3-HB), as an alternative energy source. Therefore, oral intake of 3-HB may help maintain brain health. Previous studies indicated that achieving a maximum concentration (Cmax) of 3-HB in plasma at 0.28 mM could initiate ketone metabolism in the brain; we hypothesized that attaining this Cmax would improve brain health.
Methods: We aimed to demonstrate the efficacy of an optimized single oral dose of 3-HB on cognitive function and mood through two clinical studies: a pharmacokinetic study and an efficacy study. In the pharmacokinetic study, healthy subjects were ingested 2 and 4 g of 3-HB to construct a compartment model to predict the minimum oral dose of 3-HB needed to achieve the target Cmax. In the efficacy study, a randomized, double-blinded, and placebo-controlled crossover trial, the effects of 3-HB at the predicted doses on cognitive function and mood in healthy subjects were assessed by a serial arithmetic test (SAT), the cognitrax, the profile of mood states 2nd edition (POMS2), and fatigue visual analog scale (VAS).
Results: In the pharmacokinetic study, a one-compartment model that includes saturable and non-saturable absorption pathways, constant biosynthesis, and the linear elimination of 3-HB after oral administration were constructed. The model principally reflected the observed serum 3-HB concentrations profiles and predicted a minimum dose of 3.5 g needed to achieve the target Cmax. In the efficacy study, although no significant difference was observed in any cognitive domains assessed by the Cognitrax, total responses and correct answers in the SAT were significantly improved in the active group receiving 3.5 g of 3-HB compared to the placebo group. Regarding the POMS2, confusion-bewilderment, fatigue-inertia, vigor-activity, and total mood disturbance scales were significantly improved in the active group compared to the placebo group. Additionally, fatigue VAS were also significantly improved in the active group compared to the placebo group.
Discussion: We successfully established a one-compartment model for oral 3-HB intake and demonstrated partial efficacy on cognitive function and broad efficacy on mood in healthy subjects with a single oral dose of 3.5 g of 3-HB optimized by the model.
期刊介绍：
No subject pertains more to human life than nutrition. The aim of Frontiers in Nutrition is to integrate major scientific disciplines in this vast field in order to address the most relevant and pertinent questions and developments. Our ambition is to create an integrated podium based on original research, clinical trials, and contemporary reviews to build a reputable knowledge forum in the domains of human health, dietary behaviors, agronomy & 21st century food science. Through the recognized open-access Frontiers platform we welcome manuscripts to our dedicated sections relating to different areas in the field of nutrition with a focus on human health.
Specialty sections in Frontiers in Nutrition include, for example, Clinical Nutrition, Nutrition & Sustainable Diets, Nutrition and Food Science Technology, Nutrition Methodology, Sport & Exercise Nutrition, Food Chemistry, and Nutritional Immunology. Based on the publication of rigorous scientific research, we thrive to achieve a visible impact on the global nutrition agenda addressing the grand challenges of our time, including obesity, malnutrition, hunger, food waste, sustainability and consumer health.
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