Effects of Retinoids on CYP2D6 Activity and Variability in Special Populations

项目摘要 CYP 2D 6是一种关键的药物代谢酶，参与约20%的药物代谢。我们 假设肝脏中视黄酸浓度和类维生素A信号传导自然变化 调节CYP 2D 6在人体中的表达和活性，这反过来又有助于CYP 2D 6 妊娠期间的药代动力学变异性和CYP 2D 6诱导。我们将采取一种机械的 在2项评价类维生素A浓度和CYP 2D 6活性的研究中， 从妊娠期间CYP 2D 6诱导的角度来看，维生素A抑制诱导 在非糖尿病患者中使用13-顺式-视黄酸（异维甲酸）给药并抑制正常的CYP 2D 6活性， 怀孕的青少年患者孕妇和青少年患者经常需要治疗慢性 条件，其可包括CYP 2D 6底物。考虑到遗传变异， 在这些特殊人群中，CYP 2D 6活性存在大量无法解释的变异性， 挑战性基础科学研究表明，类维生素A在CYP 2D 6调节中发挥重要作用。我们 目的了解维甲酸对妊娠、产后及青春期CYP 2D 6活性的影响 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。确定怀孕期间服用维生素A是否会降低CYP 2D 6活性。 为此，我们将评估维生素A给药对妊娠诱导的CYP 2D 6活性的影响。这 研究将提供妊娠期间CYP 2D 6诱导和变异的机制理解， 为需要CYP 2D 6底物的妊娠女性的管理提供了潜在的临床策略。 具体目标2。研究异维甲酸（13-顺式-维甲酸）给药是否会降低CYP 2D 6 青少年患者的活动。为此，我们将进行一项药物相互作用研究， 13-顺式维甲酸对青少年患者非诱导性CYP 2D 6活性的影响。次要分析将 评估这些特殊人群中类维生素A浓度与CYP 2D 6活性之间的关系。在 两个特定目的，我们将使用美沙芬作为我们的CYP 2D 6探针底物。通过这些 互补的目的，我们将是第一个进行机制测试的内源性调控CYP 2D 6 人类的活动。这些结果可以克服安全有效地给予CYP 2D 6的关键障碍 青少年和妊娠患者的基质。根据我们令人信服的初步数据，我们预计 确定人类CYP 2D 6调节新机制和潜在的管理策略 妊娠期间的CYP 2D 6诱导和变异性，目的是提高 为这些脆弱的患者提供治疗。这项工作对于提供个性化治疗至关重要， 沿着遗传学，是开发CYP 2D 6活性内源性生物标志物的第一步。

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.