Effects of Retinoids on CYP2D6 Activity and Variability in Special Populations

类维生素A对特殊人群中CYP2D6活性和变异性的影响

• 批准号: 9904729
• 负责人: MARY F HEBERT
• 金额: $ 54.99万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904729
• 关键词: Accounting; Adolescent; Animal Model; Basic Science; Biological Availability; Biological Markers; CYP2D6 gene; Chronic; Clinical; Clinical Management; Coughing; Cytochrome P450; Data; Development; Dextromethorphan; Dextrorphan; Diet; Drug Interactions; Drug Kinetics; Drug toxicity; Enzyme Induction; Enzymes; Exhibits; Genetic; Genetic Transcription; Genetic Variation; Genotype; Grant; Hepatocyte; Human; Hydroxylation; In Vitro; Individual; Intention; Intervention; Isotretinoin; Laboratory Finding; Late pregnancy; Lead; Liver; Mediating; Metabolism; Metoprolol; Oral; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Plasma; Play; Postpartum Period; Pregnancy; Pregnant Women; Regulation; Repression; Research; Retinoids; Role; Safety; Signal Transduction; Testing; Transgenic Organisms; Translating; Tretinoin; Variant; Vitamin A; Vulnerable Populations; Work; adolescent patient; base; demethylation; enzyme mechanism; human data; humanized mouse; improved; in vivo; individualized medicine; mouse model; named group; novel; pregnant; pregnant teen; secondary analysis; urinary

PROJECT SUMMARY CYP2D6, a key drug-metabolizing enzyme, is involved in the metabolism of ~20% of all drugs. We hypothesize that natural variation in retinoic acid concentrations and retinoid signaling in the liver regulate CYP2D6 expression and activity in humans, which in turn contributes to CYP2D6 pharmacokinetic variability and CYP2D6 induction during pregnancy. We will take a mechanistic approach and test the relationship between retinoid concentrations and CYP2D6 activity in 2 studies evaluating from the perspective of CYP2D6 induction during pregnancy, repression of induction with vitamin A administration and repression of normal CYP2D6 activity with 13-cis-retinoic acid (isotretinoin) in non- pregnant adolescent patients. Pregnant and adolescent patients often require treatment for chronic conditions, which can include CYP2D6 substrates. After accounting for genetic variation, there is still a great deal of unaccounted variability in CYP2D6 activity in these special populations making clinical management challenging. Basic science studies suggest that retinoids play an important role in CYP2D6 regulation. Our objective is to understand the role of retinoids in CYP2D6 activity in pregnant, postpartum and adolescent patients and translate new laboratory findings into humans. Our Specific Aims are: Specific Aim 1. To determine if vitamin A administration decreases CYP2D6 activity during pregnancy. In this aim, we will evaluate the effect of vitamin A administration on pregnancy-induced CYP2D6 activity. This study will provide mechanistic understanding of CYP2D6 induction and variability during pregnancy as well as provide a potential clinical strategy for management of pregnant women that require CYP2D6 substrates. Specific Aim 2. To investigate if isotretinoin (13-cis-retinoic acid) administration decreases CYP2D6 activity in adolescent patients. In this aim, we will conduct a drug-drug interaction study evaluating the effects of 13-cis-retinoic acid on non-induced CYP2D6 activity in adolescent patients. Secondary analysis will evaluate the relationship between retinoid concentrations and CYP2D6 activity in these special populations. In both Specific Aims we will utilize dextromethorphan as our CYP2D6 probe substrate. Through these complementary aims, we will be the first to conduct mechanistic testing of endogenous regulation of CYP2D6 activity in humans. The results could overcome a critical barrier to safe and effective administration of CYP2D6 substrates in adolescent and pregnant patients. Based on our compelling preliminary data, we expect to identify a novel mechanism of CYP2D6 regulation in humans and a potential management strategy for CYP2D6 induction and variability during pregnancy, with the intention of improving safety and efficacy of medications for these vulnerable patients. This work is critical for the provision of individualized therapy and along with genetics, the first step in development of an endogenous biomarker for CYP2D6 activity.

项目摘要 CYP2D6是一种关键的药物代谢酶，与约20％的所有药物的代谢有关。我们 假设视黄酸浓度和肝脏中视黄素信号的自然变化 调节人类的CYP2D6表达和活性，这反过来促进CYP2D6 妊娠期间的药代动力学变异性和CYP2D6诱导。我们将采取机械 在2项评估的研究中，类维生素性浓度与CYP2D6活性之间的关系 从怀孕期间CYP2D6诱导的角度来抑制维生素A 用13-钙摩酸（异托丁者）在非 - 怀孕的青春期患者。怀孕和青春期患者通常需要治疗慢性 条件，其中可能包括CYP2D6底物。考虑到遗传变异后，仍然有一个很好的 在这些特殊人群中，CYP2D6活动中无关可变性的交易交易使临床管理 具有挑战性的。基础科学研究表明，类视网膜类动物在CYP2D6调节中起重要作用。我们的 目的是了解性类维生素类动物在CYP2D6活性中的作用在孕妇，产后和青少年 患者并将新的实验室发现转化为人类。我们的具体目的是： 具体目的1。确定维生素A给药是否会在怀孕期间降低CYP2D6的活性。 在此目标中，我们将评估维生素A给药对妊娠诱导的CYP2D6活性的影响。这 研究将提供对怀孕期间CYP2D6诱导和可变性的机械理解以及 为需要CYP2D6底物的孕妇的管理提供了潜在的临床策略。 具体目标2。要研究异维使用诺（13-钙摩酸）的给药是否会降低CYP2D6 青春期患者的活性。在此目的中，我们将进行一项评估药物的药物相互作用研究 13-钙摩酸对青少年患者非诱导的CYP2D6活性的影响。次级分析将 评估类视感浓度与CYP2D6活性之间的关系。在 这两个具体目的我们都将利用右美甲泛源作为我们的CYP2D6探针底物。通过这些 互补的目的，我们将是第一个进行CYP2D6内源性调节机械测试的人 人类的活动。结果可能会克服安全有效给药CYP2D6的关键障碍 青少年和孕妇的底物。根据我们引人入胜的初步数据，我们希望 确定人类中CYP2D6调节的新型机制，以及潜在的管理策略 CYP2D6怀孕期间的诱导和可变性，目的是提高安全性和功效 这些脆弱患者的药物。这项工作对于提供个性化疗法和 与遗传学一起，开发用于CYP2D6活性的内源性生物标志物的第一步。

项目成果

Effects of Pregnancy on Plasma Sphingolipids Using a Metabolomic and Quantitative Analysis Approach.

• DOI: 10.3390/metabo13091026
• 发表时间: 2023-09-21
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Enthoven LF;Shi Y;Fay E;Kim A;Moreni S;Mao J;Isoherranen N;Totah RA;Hebert MF
• 通讯作者: Hebert MF