Assessment of celecoxib poly(lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats.
Assessment of celecoxib poly(lactic-co-glycolic) acid nanoformulation on drug pharmacodynamics and pharmacokinetics in rats.
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发表时间：
2016-11
影响因子：
3.3
通讯作者：
S. Harirforoosh;West Ko;D. Murrell;James W. Denham;P. Panus;Gregory Hanley
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作者：
S. Harirforoosh;West Ko;D. Murrell;James W. Denham;P. Panus;Gregory Hanley
塞来昔布（CEL）是一种非甾体抗炎药（NSAID），具有选择性环氧化酶-2抑制作用。CEL作为一种有效的止痛剂，对肾脏和胃肠道参数有一定的负面影响。本研究检测了以聚（乳酸-羟基乙酸）酸纳米颗粒（NP）形式重新配制药物后的CEL药效学和药代动力学。材料与方法将大鼠分别给予对照物（VEH）（甲基纤维素溶液）、空白NP、40 mg/kg甲基纤维素中的CEL或等效NP剂量（CEL-NP）。在治疗前后收集血浆和尿液（超过12小时）样本。以100g体重为基准，评估尿流率与血浆和尿液中电解质浓度的平均变化百分比。使用治疗后24小时收集的组织，通过十二指肠和胃前列腺素E2 （PGE2）和十二指肠髓过氧化物酶（MPO）水平评估胃肠道炎症；同时检查肾脏组织是否扩张和坏死。采用高效液相色谱法测定肾组织和血浆中CEL浓度。结果虽然CEL和CEL- np与VEH比较血浆钠浓度和钾排泄率有显著变化，但CEL和CEL- np之间无显著差异。与VEH （p = 0.0088）和CEL- np （p = 0.02）相比，CEL组的保护性十二指肠PGE2显著降低。在CEL- np配方中，t1/2、Cmax、AUC0-∞和Vd/F较CEL显著增加。结论：在观察到的剂量和持续时间内，CEL-NP可能不会影响血浆或尿液中cel相关的电解质参数；然而，它确实增加了全身暴露，同时可能减轻一些与炎症相关的胃肠道后果。
OBJECTIVE Celecoxib (CEL) is a nonsteroidal anti-inflammatory drug (NSAID) showing selective cycloxygenase-2 inhibition. While effective as a pain reducer, CEL exerts some negative influence on renal and gastrointestinal parameters. This study examined CEL pharmacodynamics and pharmacokinetics following drug reformulation as a poly(lactic-co-glycolic) acid nanoparticle (NP). MATERIALS AND METHODS Rats were administered either vehicle (VEH) (methylcellulose solution), blank NP, 40 mg/kg CEL in methylcellulose, or an equivalent NP dose (CEL-NP). Plasma and urine (over 12 hrs) samples were collected prior to and post-treatment. The mean percent change from baseline of urine flow rate along with electrolyte concentrations in plasma and urine were assessed based on 100 g body weight. Using tissues collected 24 hrs post-treatment, gastrointestinal inflammation was estimated through duodenal and gastric prostaglandin E2 (PGE2) and duodenal myeloperoxidase (MPO) levels; while kidney tissue was examined for dilatation and necrosis. CEL concentration was assayed in renal tissue and plasma utilizing high-performance liquid chromatography. RESULTS Although there were significant changes when comparing CEL and CEL-NP to VEH in plasma sodium concentration and potassium excretion rate, there was no significant variation between CEL and CEL-NP. There was a significant reduction of protective duodenal PGE2 in CEL compared to VEH (p = 0.0088) and CEL-NP (p = 0.02). In the CEL-NP formulation, t1/2, Cmax, AUC0-∞, and Vd/F increased significantly when compared to CEL. CONCLUSIONS At the observed dosage and duration, CEL-NP may not affect CEL-associated electrolyte parameters in either plasma or urine; however, it does provide increased systemic exposure while potentially alleviating some gastrointestinal outcomes related to inflammation.