Microdialysis coupled to an analytical system can be used to continuously monitor unbound protein analytes in any biological fluid, tissue, or organ of animals. To date, no application of microdialysis has been performed to simultaneously monitor unbound morphine and its metabolites in the placenta and fetus of pregnant rats. Our hypothesis is that morphine and its metabolite penetrate the blood–placental barrier to reach the fetus during pregnancy. To investigate this hypothesis, this study aimed to develop a microdialysis experimental animal model coupled with an analytical system to monitor morphine and morphine-3-glucuronide (M3G) in the maternal blood, placenta, fetus, and amniotic fluid of pregnant rats. To determine the analytes in dialysates, a validated ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method was developed. The pharmacokinetic results indicated that morphine fit well to a two-compartment model and exhibited nonlinear pharmacokinetic behavior within the dosage regimen. The M3G-to-morphine metabolite ratio, determined by the area under the concentration curve (AUC) ratio (AUC_M3G/AUC_morphine), was approximately 5.40 in the maternal blood. In terms of tissue distribution, the mother-to-fetus transfer ratio (AUC_fetus/AUC_blood) of morphine and M3G was about 0.34 and 0.18, respectively. In conclusion, the high metabolite ratio suggests that morphine has the characteristics of rapid biotransformation, and the mother-to-fetus transfer ratio indicates that morphine and M3G partially transfer the blood–placental barrier in pregnant rats. This newly developed multiple microdialysis coupled to UHPLC-MS/MS system can be applied to the studies of maternal pharmacokinetics and blood–placental transfer in pregnant rats.

中文翻译：

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多微透析系统妊娠大鼠血胎盘屏障转移和未结合吗啡的药代动力学

与分析系统耦合的微透析可用于连续监测任何生物体液、组织或动物器官中的未结合蛋白质分析物。迄今为止，尚未应用微透析同时监测怀孕大鼠胎盘和胎儿中未结合的吗啡及其代谢物。我们的假设是，在怀孕期间，吗啡及其代谢物会穿透血-胎盘屏障到达胎儿体内。为了研究这一假设，本研究旨在开发一种微透析实验动物模型，并结合分析系统监测妊娠大鼠母体血液、胎盘、胎儿和羊水中的吗啡和吗啡-3-葡糖苷酸 (M3G)。要确定透析液中的分析物，开发了一种经过验证的超高效液相色谱-串联质谱 (UHPLC-MS/MS) 方法。药代动力学结果表明吗啡非常适合二室模型，并且在给药方案中表现出非线性药代动力学行为。M3G 与吗啡代谢物的比率，由浓度曲线下面积 (AUC) 比率 (AUC) 确定_M3G /AUC_吗啡）在母体血液中约为 5.40。在组织分布方面，吗啡和M3G的母婴移植比（AUC_胎儿/AUC_血液）分别约为0.34和0.18。综上所述，高代谢物比值提示吗啡具有快速生物转化的特点，母胎转移比值表明吗啡和M3G部分转移妊娠大鼠的血-胎盘屏障。这种新开发的多重微透析与 UHPLC-MS/MS 系统耦合可应用于妊娠大鼠母体药代动力学和血液-胎盘转移的研究。