Pharmacokinetics of Inter-Alpha Inhibitor Proteins and Effects on Hemostasis After Hypoxic-Ischemic Brain Injury in Neonatal Rats.
Pharmacokinetics of Inter-Alpha Inhibitor Proteins and Effects on Hemostasis After Hypoxic-Ischemic Brain Injury in Neonatal Rats.
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DOI：
10.2174/1381612826666200421123242
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发表时间：
2020
影响因子：
3.1
通讯作者：
Stonestreet BS
中科院分区：
文献类型：
--
作者：
Chen X;Song D;Nakada S;Qiu J;Iwamoto K;Chen RH;Lim YP;Jusko WJ;Stonestreet BS
缺氧缺血性（HI）脑损伤是新生儿长期神经发育疾病的主要原因。人血浆衍生的 Inter-Alpha 抑制蛋白 (hIAIP) 在新生大鼠 HI 脑损伤后具有神经保护作用。 hIAIP 的轻链（bikunin）抑制参与血液凝固的蛋白酶。接触HI 的新生儿可能面临大脑和其他器官严重出血的风险。本研究的目的是评估 HI 暴露的雄性和雌性新生大鼠腹腔 (IP) 施用 hIAIP 后的药代动力学 (PK) 和出血持续时间。采用 Rice-Vannucci 法在出生后 (P) 第 7 天的大鼠中诱导 HI。右侧颈总动脉结扎后，将大鼠置于8%氧气中90分钟。在 PK 研究中，在假手术或 HI 暴露后立即给予 hIAIP（30 mg/kg，IP），并在注射后 1、6、12、24 或 36 小时收集血清。使用竞争性 ELISA 测量血清 hIAIP 浓度。考虑一级吸收和处置，使用 ADAPT5 软件拟合合并的 PK 数据。在 HI 后 0、24 和 48 小时的出血时间研究中给予 hIAIP（60 mg/kg，IP），并在 HI 后 72 小时测量尾部出血时间。 IP 给药导致 hIAIP 显着全身暴露，PK 受到显着影响，主要包括由于 HI 导致吸收加快和消除减少，以及由于性别相关差异而适度影响。此外，hIAIP 给药不会影响 HI 后的出血时间。这些结果将有助于为暴露于 HI 的新生儿的神经保护研究中的 hIAIP 给药方案提供信息。
Hypoxic-ischemic (HI) brain injury is a leading cause of long-term neurodevelopmental morbidities in neonates. Human plasma-derived Inter-Alpha Inhibitor Proteins (hIAIPs) are neuroprotective after HI brain injury in neonatal rats. The light chain (bikunin) of hIAIPs inhibits proteases involved in the coagulation of blood. Newborns exposed to HI can be at risk for significant bleeding in the brain and other organs. The objectives of the present study were to assess the pharmacokinetics (PK) and the duration of bleeding after intraperitoneal (IP) administration of hIAIPs in HI-exposed male and female neonatal rats. HI was induced with the Rice-Vannucci method in postnatal (P) day-7 rats. After the right common carotid artery ligation, rats were exposed to 90 min of 8% oxygen. hIAIPs (30 mg/kg, IP) were given immediately after Sham or HI exposure in the PK study and serum was collected 1, 6, 12, 24, or 36 h after the injections. Serum hIAIP concentrations were measured with a competitive ELISA. ADAPT5 software was used to fit the pooled PK data considering first-order absorption and disposition. hIAIPs (60 mg/kg, IP) were given in the bleeding time studies at 0, 24 and 48 h after HI with tail bleeding times measured 72 h after HI. IP administration yielded significant systemic exposure to hIAIPs with PK being affected markedly including primarily faster absorption and reduced elimination as a result of HI and modestly because of sex-related differences. Besides, hIAIP administration did not affect bleeding times after HI. These results will help to inform hIAIP dosing regimen schedules in studies of neuroprotection in neonates exposed to HI.