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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要 CYP2D6 是一种关键的药物代谢酶，参与约 20% 的药物的代谢。我们假设肝脏中视黄酸浓度和类视黄醇信号传导存在自然变化调节人类 CYP2D6 的表达和活性，进而促进 CYP2D6 妊娠期间的药代动力学变异性和 CYP2D6 诱导。我们将采取机械化的方式在 2 项评估研究中方法并测试了类视黄醇浓度与 CYP2D6 活性之间的关系从怀孕期间CYP2D6诱导的角度来看，用维生素A抑制诱导使用 13-顺式视黄酸（异维A酸）在非怀孕的青少年患者。怀孕和青少年患者经常需要治疗慢性病条件，其中可以包括 CYP2D6 底物。考虑到遗传变异后，仍然存在很大的差异。这些特殊人群中 CYP2D6 活性的未解释的变异性使得临床管理具有挑战性的。基础科学研究表明类视黄醇在 CYP2D6 调节中发挥重要作用。我们的目的是了解类视黄醇在怀孕、产后和青少年 CYP2D6 活性中的作用患者并将新的实验室发现转化为人类。我们的具体目标是：具体目标 1. 确定服用维生素 A 是否会降低怀孕期间 CYP2D6 的活性。为此，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 诱导和变异的机制理解以及为需要 CYP2D6 底物的孕妇的管理提供潜在的临床策略。具体目标 2. 研究异维A酸（13-顺-视黄酸）给药是否会降低 CYP2D6 青少年患者的活动。为此，我们将进行药物相互作用研究，评估 13-顺式视黄酸对青少年患者非诱导 CYP2D6 活性的影响。二次分析将评估这些特殊人群中视黄醇浓度与 CYP2D6 活性之间的关系。在为了实现这两个具体目标，我们将利用右美沙芬作为 CYP2D6 探针底物。通过这些互补的目标，我们将率先对 CYP2D6 的内源性调控进行机制测试在人类中的活动。结果可以克服安全有效施用 CYP2D6 的关键障碍青少年和孕妇的底物。根据我们令人信服的初步数据，我们预计确定人类 CYP2D6 调节的新机制以及潜在的管理策略妊娠期间 CYP2D6 的诱导和变异，旨在提高安全性和有效性为这些弱势患者提供药物。这项工作对于提供个体化治疗和与遗传学一起，这是开发 CYP2D6 活性内源生物标志物的第一步。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

使用代谢组学和定量分析方法研究妊娠对血浆鞘脂的影响。

DOI：
发表时间：
2023-09-21
期刊：
影响因子：
4.1
作者：
Enthoven, Luke F;Shi, Yuanyuan;Fay, Emily;Kim, Agnes;Moreni, Sue;Mao, Jennie;Isoherranen, Nina;Totah, Rheem A;Hebert, Mary F
通讯作者：
Hebert, Mary F

CYP2D6 Activity Is Correlated with Changes in Plasma Concentrations of Taurocholic Acid during Pregnancy and Postpartum in CYP2D6 Extensive Metabolizers.

CYP2D6 活性与妊娠期和产后 CYP2D6 粗代谢者血浆牛磺胆酸浓度的变化相关。

DOI：
发表时间：
2023-11
期刊：
影响因子：
0
作者：
Czuba, Lindsay C;Malhotra, Karan;Enthoven, Luke;Fay, Emily E;Moreni, Sue L;Mao, Jennie;Shi, Yuanyuan;Huang, Weize;Totah, Rheem A;Isoherranen, Nina;Hebert, Mary F
通讯作者：
Hebert, Mary F

Plasma hydrogen sulfide, nitric oxide, and thiocyanate levels are lower during pregnancy compared to postpartum in a cohort of women from the Pacific northwest of the United States.

来自美国西北部太平洋地区的一组妇女在怀孕期间血浆硫化氢、一氧化氮和硫氰酸盐水平低于产后。