Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
J Pharmacol Exp Ther. 2011 Oct;339(1):275-85. doi: 10.1124/jpet.111.183855. Epub 2011 Jul 20.
Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited >80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0-57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.
关于抗抑郁药暴露后胎儿中枢神经系统（CNS）暴露的严格数据稀少。使用血清素转运蛋白（SERT）的体外放射自显影技术，在三组大鼠中测量了血清素再摄取抑制剂（SRI）对中枢神经系统的暴露程度：1）子宫内，2）出生后的清除情况，以及3）通过哺乳的暴露情况。大鼠通过渗透微型泵持续接受五种SRI类抗抑郁药（艾司西酞普兰、氟西汀、帕罗西汀、舍曲林和文拉法辛）中的一种，给药对象为怀孕或哺乳的母鼠。调整母鼠的给药剂量以反映孕妇中观察到的血清浓度的第50和第85百分位数。在子宫内暴露的胚胎第21天的幼鼠，其脑组织中的SERT占有率>80%，这与怀孕母鼠相当，并且与人类药物治疗的报道相似。文拉法辛是个例外，不同窝的占有率在61%至92%之间。母鼠和胎儿之间的SERT占有率基本相当。到出生后第4天，仅在暴露于氟西汀的幼鼠中观察到高SERT占有率（占有率为41%-92%）。即使在哺乳幼鼠血清中未检测到药物浓度，通过母乳暴露也会发生明显较少但可测量的暴露。通过母乳暴露于SRI 3天或7天的幼鼠表现出不同的SERT占有率（0%-57%，取决于具体药物和母鼠剂量）。这些数据凸显了使用具有临床意义的给药策略和适当的中枢神经系统测量方法对胎儿和哺乳婴儿药物暴露进行动物建模的必要性，以便制定合理的治疗指南，系统性地减少人类胎儿和新生儿的药物暴露。
