Departament of Pharmacology, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico City, Mexico.
Hospital General de México Dr. Eduardo Liceaga, Mexico City, Mexico.
Naunyn Schmiedebergs Arch Pharmacol. 2020 Mar;393(3):395-404. doi: 10.1007/s00210-019-01745-9. Epub 2019 Oct 22.
Previous reports have warned about the influence of spinal cord injury (SCI) on the pharmacokinetics of various drugs. However, the role of SCI in the efficacy and safety of pharmacotherapy remains unknown. Thereby, our aim was to explore the role of SCI on pharmacokinetics and anti-inflammatory effect of naproxen in response to a local inflammatory challenge. Rats received a severe contusive SCI at T9 or sham injury. Pharmacokinetics of a single intravenous dose of naproxen (10 mg kg) was studied at days 1 and 15 post-surgery. For the anti-inflammatory assessment, carrageenan was subcutaneously injected in forelimb and hindlimb paws at the same post-surgery periods, and naproxen efficacy was evaluated measuring paw swelling. Plasma protein concentrations and body weight changes were also determined. Plasma naproxen levels and pharmacokinetic parameters were unchanged by acute injury, but subacute injury generated alterations in volume of distribution, clearance, and bioavailability, resulting in significantly reduced plasma naproxen concentrations, in the absence of changes in plasma proteins. Assessment of naproxen anti-inflammatory activity during the acute stage of injury could not be determined because of carrageenan failure to elicit swelling. During the subacute stage, naproxen anti-inflammatory effect on forelimbs (above injury) was similar to that observed in sham-injured animals, while it was almost absent in paralyzed hindlimbs. Under conditions of SCI and peripheral inflammation, pharmacokinetics and anti-inflammatory activity of naproxen vary according to post-injury timing and neurological status of the assessed region.
先前的报告已经警告过脊髓损伤 (SCI) 对各种药物药代动力学的影响。然而，SCI 对药物治疗效果和安全性的作用仍然未知。因此，我们的目的是探讨 SCI 对塞来昔布在局部炎症反应中的药代动力学和抗炎作用的影响。大鼠在 T9 处接受严重的挫伤性 SCI 或假损伤。在手术后第 1 天和第 15 天研究了单次静脉注射塞来昔布（10 mg/kg）的药代动力学。为了评估抗炎作用，在相同的手术后时期向前后肢爪子皮下注射角叉菜胶，并通过测量爪子肿胀来评估塞来昔布的疗效。还测定了血浆蛋白浓度和体重变化。急性损伤并未改变血浆塞来昔布水平和药代动力学参数，但亚急性损伤改变了分布容积、清除率和生物利用度，导致血浆塞来昔布浓度显著降低，而血浆蛋白没有变化。由于角叉菜胶未能引起肿胀，因此无法在损伤的急性阶段评估塞来昔布的抗炎活性。在亚急性阶段，塞来昔布对前肢（损伤以上）的抗炎作用与假损伤动物观察到的相似，而在瘫痪的后肢中几乎不存在。在 SCI 和周围炎症的情况下，塞来昔布的药代动力学和抗炎活性根据受伤后的时间和评估区域的神经状态而变化。
