Placental Transfer, Pharmacokinetics and Cardiovascular Effects of Dexmedetomidine in Pregnant Ewe and Fetus



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Purpose and Specific Aims: Anesthetic agents used for pregnant mothers have been evaluated in an attempt to improve the safety of maternal-fetal anesthesia. Dexmedetomidine (DEX; Precedex®), a potent and highly selective α2-adrenoceptor agonist approved by FDA in 1999 as a sedative, has been suggested to be suitable for maternal-fetal anesthesia. It offers significant sedative, analgesic and anxiolytic effects without causing respiratory depression. The mechanism of DEX action mediated by signaling pathways other than the α2-adrenoceptor has been reported to play a role in neuroprotection. Animal studies have indicated that DEX could provide neuroprotective effects on anesthetic-induced neurotoxicity in neonatal rats. However, the impact of maternal use of DEX that may be associated with hypotension and bradycardia on fetal development during pregnancy is not fully understood; this greatly limits its usage in pregnant women. Our proposed research has focused on the investigation of fetal exposure and response to the maternal use of DEX during pregnancy. In this study, pregnant ewe was selected as an experimental model due to the ethical issues in performing experiments on human fetuses. Pregnant ewe has been an extensively used model for human pregnancy due to its main advantage that the relatively large size of the fetus enables catheters implantation in both maternal and fetal blood vessels for repeated sampling. Towards our goal, three major specific aims were proposed to: (1) determine the DEX exposure and cardiovascular response in pregnant ewe and fetus, as well as the extent of placental transfer; (2) investigate the degree of plasma protein binding and UDP-glucuronosyltransferase (UGT) metabolism in pregnant ewe and fetus; and (3) establish pharmacokinetic (PK) model and pharmacodynamic (PD) model of cardiovascular effects in pregnant ewe and fetus.

Methods: Surgeries and catheterizations were carried out on eight pregnant Western Cross ewes at the Texas Children’s Hospital, Baylor College of Medicine. Pregnant ewes received an initial 1 µg/kg loading infusion over 10 min followed by an intravenous (IV) infusion of 1 µg/kg/h for 1 h. Arterial and venous blood samples were collected at 10 min up to 250 min from both pregnant ewe and fetus. Free and total DEX plasma concentrations were quantified by our developed and validated LC-MS/MS assay. Non-compartmental PK analysis was performed to determine the partition coefficient from pregnant ewe to fetus (KFM), followed by the PK analysis using non-linear mixed effect (NLME) approach to describe the free and total DEX concentrations in the pregnant ewe and fetus. Maternal and fetal heart rates (HR) and arterial blood pressure (BP) were monitored. In vitro UGT metabolism studies with liver and placental microsomes were also conducted.

Results: DEX concentrations in maternal artery and fetal vein were 815.1±497.2 and 104.4±40.3 pg/mL at 10 min. KFM were 0.13 ± 0.10 and 0.23 ± 0.14 at 10 min and 250 min, respectively. A two-compartment model with first-order elimination best described the maternal data. An effect compartment linked to maternal circulation by first-order processes adequately characterized fetal concentrations. The relationship between free and total concentrations was satisfactorily described by linear protein binding model. For cardiovascular effects, pregnant ewes demonstrated a 30-40% decrease in BP and significant bradycardia with a 42-49% decrease in HR. In contrast, hypotension was not observed and only a modest decrease in heart rate was noted in fetuses. In vitro metabolism studies found negligible DEX glucuronide metabolites after incubation for up to 24 h with hepatic and placental microsomes prepared from the pregnant ewe and fetus. Differential UGT enzyme activity in hepatic microsomes between pregnant ewe and fetus was determined using genistein as a typical known UGT substrate. It was demonstrated that pregnant ewe has 17 times higher UGT enzyme capacity than that in the fetus.

Conclusion and Significance: The contribution of our study is a better understanding of fetal exposure and cardiovascular response to maternal administration of DEX in pregnant ewes. We have demonstrated that 1) DEX can rapidly cross pregnant ewe placenta with KFM of 23% to fetuses; (2) administration of DEX to pregnant ewe does not result in fetal hypotension or significant bradycardia; (3) in pregnant ewe DEX undergoes rapid distribution and a relatively slow elimination after administration; (4) fetus has lower plasma protein binding than that in pregnant ewe based on results from PK modeling and in vitro assessments; (5) there is a differential UGT enzyme capacity between pregnant ewe and fetus; and (6) direct N-glucuronidation is a negligible metabolic pathway for DEX in pregnant ewe which differs from that in humans. Therefore, our findings in combination with other related publications support conducting additional DEX studies for its clinical utility during pregnancy, but pregnant ewe may not be a representative model for DEX phase II metabolism study in humans. Future physiological-based pharmacokinetic modeling for the prediction of human fetal exposure and response should be investigated.



Placental transfer, Pharmacokinetics, Cardiovascular effects, Dexmedetomidine, Pregnant ewe


Portions of this document appear in: Cui, Z., DS-L. Chow, L. Wu, D. A. Lazar, R. Rodrigo, O. O. Olutoye, and O. A. Olutoye. "High performance liquid chromatography–tandem mass spectrometric assay of dexmedetomidine in plasma, urine and amniotic fluid samples for pregnant ewe model." Journal of Chromatography B 961 (2014): 13-19.