Pharmacokinetics of SSRIs in Pregnancy

描述（由申请人提供）：NICHD妊娠和围产期科的战略计划（2005-2010）将妊娠用药研究作为其使命的主要组成部分。缺乏知识从药物和药理学研究在怀孕明显不利孕妇和她的胎儿。我们的主要目的是探索一个新的概念，即胎儿的药物代谢在妊娠期间治疗药物的选择和使用中具有重要意义。我们研究的一个具体目的是将这种药理学策略应用于妊娠期抗抑郁药物的使用，研究两种具有不同代谢谱的选择性5 -羟色胺再摄取抑制剂（SSRI）的配置。体内方法是量化和比较怀孕狒狒体内氟西汀和舍曲林（两种SSRIs）的胎儿代谢与胎儿和母体代谢酶活性的体外测量的相关性。我们预计结果将提供有关降低抑郁孕妇及其后代的不同风险的信息。目的是尽量减少胎儿接触这些物质，无论是活性药物还是代谢物，同时为母亲提供有效的治疗。第二个具体目的是调查胎儿暴露于SSRIs会有过量血清素活性的迹象，并在停药后显示血清素能戒断的迹象的假设。临床报告表明，接受SSRIs治疗的孕妇婴儿在出生后出现血清素过量或戒断综合征。该方法将测量心率自主调节参数的变化，以及反映脑电图激活的变异性、频率和同步性变量，并将这些变化与胎儿体内活性物质的浓度联系起来。在胎儿暴露的这些相对急性期（4-12天），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谱。这项研究与公共卫生有关，因为母亲抑郁症是一种常见的精神疾病（15%至20%），如果不治疗，对母亲和婴儿都有多重风险。SSRI类药物对抑郁症非常有效；然而，由于担心对婴儿的风险，如出生时的戒断或对大脑发育的影响，使用不足。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，同时不限制对母亲抑郁症的治疗。

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.