Pharmacokinetics of SSRIs in Pregnancy

说明(由申请者提供)：NICHD妊娠和围产病学处的战略计划(2005-2010年)包括研究妊娠期间使用的药物，作为其使命的一个主要组成部分。孕期药物和药理研究知识的匮乏明显对孕妇和胎儿不利。我们的广泛目标是探索一种新的概念，即胎儿的药物代谢在妊娠期治疗药物的选择和使用中具有关键作用。我们研究的一个具体目的是将这一药理学策略应用于妊娠期间抗抑郁药物的使用，研究两种具有不同代谢特征的选择性5-羟色胺再摄取抑制剂(SSRI)的处置。体内的方法是量化和比较两种SSRI氟西汀和舍曲林在怀孕狒狒体内的胎儿代谢，以与胎儿和母体代谢酶活性的体外测量相关联。我们预计研究结果将为降低抑郁症孕妇及其后代的不同风险提供相关信息。目标是尽量减少胎儿接触这些药物或代谢物的机会，同时为母亲提供有效的治疗。第二个特定目的是调查这样一种假设，即胎儿暴露于SSRIs将出现5-羟色胺能活动过剩的迹象，并在停药后显示5-羟色胺能停用的迹象。临床报告表明，接受SSRIs治疗的孕妇的婴儿在出生后会出现5-羟色胺过多或停用的综合征。该方法将测量反映脑电激活的心率和变异性、频率和同步变量的自主调节参数的变化，并将这些变化与胎儿中活性物质的浓度联系起来。在这些相对急性(4-12天)的胎儿暴露时期，我们期望确定暴露和停药的特定生物标志物和初始剂量反应曲线。这项研究与公共卫生有关，因为产妇抑郁是一种常见的精神障碍(15%至20%)，如果不治疗，母亲和婴儿都会有多种风险。SSRI类药物对抑郁症非常有效；然而，由于担心对婴儿的风险，如出生时停药或对大脑发育的影响，使用SSRI类药物的效果不佳。研究将确定对胎儿影响最小的药物，减少对产后发育的影响，而不限制母亲抑郁症的治疗。

DESCRIPTION (provided by applicant): The Strategic Plan (2005-2010) of the Pregnancy and Perinatology Branch of the NICHD includes the study of drugs used in pregnancy as a major component of their mission. The paucity of knowledge from drug and pharmacologic research in pregnancy has markedly disadvantaged the pregnant woman and her fetus. Our broad objective is to explore the novel concept that drug metabolism by the fetus is of focal importance in selection and use of therapeutic agents during pregnancy. One specific aim of our research is to apply this pharmacologic strategy to the use of anti-depression drugs in pregnancy with studies of the disposition of two selective serotonin reuptake inhibitors (SSRI) that have different metabolic profiles. The in vivo approach is to quantify and compare fetal metabolism of fluoxetine and sertraline, two SSRIs, in the pregnant baboon for correlation with in vitro measures of fetal and maternal metabolic enzyme activity. We anticipate results will yield information relevant to reducing the divergent risks for depressed pregnant women and those for her offspring. The goal is to minimize exposure of the fetus to the agents, whether active drug or metabolite, while at the same time providing effective therapy for the mother. A second specific aim investigates the hypothesis that the fetus exposure to SSRIs will have signs of excess serotonergic activity and will show signs of serotonergic withdrawal after discontinuation of drug. Clinical reports indicate that infants of pregnant women treated with SSRIs have a syndrome of serotonin excess or withdrawl after birth. The approach will be to measure changes in parameters of autonomic regulation of heart rate and variability, frequency and synchrony variables reflective of EEG activation and to relate these changes to concentration of active agent in the fetus. In these relatively acute (4-12 d) epochs of fetal exposure we expect to identify specific biomarkers of exposure and withdrawal from the drug and initial dose response profiles. This research is relevant to public health because maternal depression is a common psychiatric disorder (15 to 20%) and associated with multiple risks for both mother and baby when untreated. SSRI type drugs are very effective for depression; yet, under used for fear of risks to babies, such as withdrawal at birth or effects on brain development. Research will identify drugs that have the least impact on the fetus, reduced impact on post-natal development without restricting treatment of maternal depression.