Kim John, Riggs K Wayne, Rurak Dan W
Department of Obstetrics and Gynecology, BC Research Institute for Children's & Women's Health, University of British Columbia, Vancouver, BC, Canada.
Drug Metab Dispos. 2004 Feb;32(2):212-21. doi: 10.1124/dmd.32.2.212.
We examined the stereoselective disposition of fluoxetine (FX) and its metabolite norfluoxetine (NFX) in five pregnant sheep. Racemic FX was administered i.v. to the ewe (50 mg) and the fetus (10 mg) on separate occasions. Maternal and fetal blood, maternal urine, and fetal amniotic and tracheal fluid samples were collected for 72 h. FX and NFX isomers were quantified by gas chromatography-mass spectrometry. They rapidly crossed the placenta [maternal to fetal area under the plasma concentration versus time curve (AUC) ratios 0.59 and 0.65, respectively]. There was significant FX stereoselectivity with S/R FX AUC ratios averaging 1.65 +/- 0.33 and 1.73 +/- 0.29 in ewe and fetus, respectively, after maternal dosing. The maternal clearance and volume of distribution were also higher for (R)-fluoxetine than for (S)-fluoxetine. FX, NFX, and their glucuronides were present in maternal urine but accounted for only 3.4% of maternal drug elimination. In contrast, NFX was not detected in the fetus after fetal FX administration, which is consistent with the absence of measurable fetal nonplacental clearance of the drug and the lack of NFX formation in fetal hepatic microsomal incubations. There was also no fetal production of FX and NFX glucuronides in vivo. Both FX and NFX were extensively and stereoselectively bound in maternal and fetal plasma, with the free fraction S/R FX ratio averaging 0.46 +/- 0.06 and 0.58 +/- 0.10 in ewe and fetus, respectively. Thus, FX exhibits extensive stereoselective disposition, which is likely due to differential plasma protein binding of the FX isomers, and there is no detectable fetal formation of NFX, FX, and NFX glucuronides.
我们研究了氟西汀（FX）及其代谢产物去甲氟西汀（NFX）在五只怀孕绵羊体内的立体选择性分布情况。在不同时间分别给母羊静脉注射消旋氟西汀（50毫克）和给胎儿静脉注射（10毫克）。在72小时内收集母羊和胎儿的血液、母羊尿液以及胎儿羊水和气管液样本。通过气相色谱 - 质谱法对FX和NFX异构体进行定量分析。它们能迅速穿过胎盘[母体到胎儿的血浆浓度 - 时间曲线下面积（AUC）比值分别为0.59和0.65]。母体给药后，在母羊和胎儿体内，FX存在显著的立体选择性，S/R - FX的AUC比值在母羊和胎儿中分别平均为1.65±0.33和1.73±0.29。（R） - 氟西汀的母体清除率和分布容积也高于（S） - 氟西汀。FX、NFX及其葡糖醛酸化物存在于母羊尿液中，但仅占母体药物消除量的3.4%。相比之下，给胎儿注射FX后，在胎儿体内未检测到NFX，这与该药物在胎儿体内无可测量的非胎盘清除以及胎儿肝微粒体孵育中缺乏NFX形成是一致的。在体内胎儿也未产生FX和NFX的葡糖醛酸化物。FX和NFX在母体和胎儿血浆中均有广泛且立体选择性的结合，游离分数S/R - FX比值在母羊和胎儿中分别平均为0.46±0.06和0.58±0.10。因此，FX表现出广泛的立体选择性分布，这可能是由于FX异构体的血浆蛋白结合存在差异，并且未检测到胎儿体内有NFX、FX和NFX葡糖醛酸化物的形成。
