Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science & Technology, Irbid, Jordan.
Nanotechnology Institute, Jordan University of Science & Technology, Irbid, Jordan.
Drug Metab Pers Ther. 2024 Aug 8;39(3):115-124. doi: 10.1515/dmpt-2024-0037. eCollection 2024 Sep 1.
The antiepileptic phenytoin has a narrow therapeutic window, nonlinear pharmacokinetics, and can cross the placenta causing apathy and jitteriness in postpartum newborns. Further, the sudden decay of phenytoin concentration can cause withdrawal seizures. This work aimed to assess the brain toxic exposure to phenytoin in newborns after transplacental transfer using neonatal saliva-brain correlations.
The phenytoin dose that the newborn receives transplacentally at birth was estimated using verified physiologically based pharmacokinetic (PBPK) model simulations in third-trimester pregnancy (pregnancy T3). Such doses were used as an input to the newborn PBPK model to estimate the neonatal levels of phenytoin and their correlations in brain extracellular fluid (bECF), plasma, and saliva.
The PBPK model-estimated neonatal plasma and bECF concentrations of phenytoin were below the necessary thresholds for anticonvulsant and toxic effects. The neonatal salivary thresholds for phenytoin anticonvulsant and toxic effects were estimated to be 1.3 and 2.5 mg/L, respectively using the plasma-saliva-bECF correlations established herein.
The salivary TDM of phenytoin can be a more convenient option for avoiding phenytoin brain toxicity in newborns of epileptic mothers. Still, the appropriateness of using the same adult values of phenytoin anticonvulsant and toxic effects for infants needs investigation.
抗癫痫药物苯妥英的治疗窗较窄，药代动力学呈非线性，可透过胎盘，导致产后新生儿出现冷漠和紧张。此外，苯妥英浓度的突然下降可引起戒断性癫痫发作。本研究旨在通过新生儿唾液-脑相关性评估经胎盘转移后新生儿苯妥英的脑毒性暴露情况。
使用第三孕期（妊娠 T3）验证的基于生理学的药代动力学（PBPK）模型模拟来估计新生儿在出生时经胎盘接受的苯妥英剂量。将这些剂量用作新生儿 PBPK 模型的输入，以估计新生儿的苯妥英水平及其在脑细胞外液（bECF）、血浆和唾液中的相关性。
PBPK 模型估计的新生儿血浆和 bECF 中的苯妥英浓度低于抗惊厥和毒性作用所需的阈值。使用本文建立的血浆-唾液-bECF 相关性，估计新生儿苯妥英抗惊厥和毒性作用的唾液阈值分别为 1.3 和 2.5mg/L。
对于患有癫痫的母亲的新生儿，苯妥英的唾液治疗药物监测（TDM）可能是一种更方便的避免苯妥英脑毒性的选择。然而，对于婴儿是否可以使用与成人相同的苯妥英抗惊厥和毒性作用值，仍需要进一步研究。
