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Reduced Heart Exposure of Diclofenac by Its Polymeric Micellar Formulation Normalizes CYP-Mediated Metabolism of Arachidonic Acid Imbalance in An Adjuvant Arthritis Rat Model: Implications in Reduced Cardiovascular Side Effects of Diclofenac by Nanodrug Delivery.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.molpharmaceut.0c00069 Hanan Al-Lawati 1 , Mohammad Reza Vakili 1 , Afsaneh Lavasanifar 1 , Surur Ahmed 1 , Fakhreddin Jamali 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.molpharmaceut.0c00069 Hanan Al-Lawati 1 , Mohammad Reza Vakili 1 , Afsaneh Lavasanifar 1 , Surur Ahmed 1 , Fakhreddin Jamali 1
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In this study, we tested whether the extent of drug presence in the heart contributes to the elevated cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs). A fluorescently tagged nanoformulation of an NSAID with high cardiovascular (CV) risk (diclofenac) was developed as diclofenac ethyl ester (DFEE) encapsulated in traceable (cyanine-5.5-labeled) polymeric micelles (DFEE-TM) based on methoxypoly(ethylene oxide)-block-poly(ε-caprolactone)(PEO-b-PCL) (MW, 5000:3500 g/mol). Diclofenac pharmacokinetics and tissue distribution, as well as ex vivo near-infrared images of organs and whole bodies, were compared between healthy rats and rats with adjuvant arthritis (AA) following the administration of a single intravenous (iv) dose of DFEE-TM. Moreover, the biodistribution and antiarthritic activity of DFEE-TM were compared with those of free diclofenac (once-daily intraperitoneal, ip, 10 mg/kg for 7 days). The concentration ratios of cytochrome-P450-mediated cardiotoxic (20-hydroxyeicosatetraenoic acid) over cardioprotective (epoxyeicosatrienoic acids) metabolites of arachidonic acid (ArA) in the heart, kidneys, and plasma were measured as markers of cardiotoxicity. The nanocarrier was found in the joints of AA, but not in those of healthy rats. Both free diclofenac and DFEE-TM comparably controlled AA. Diclofenac delivery via PEO-b-PCL micelles reduced the accumulation of diclofenac in the heart of AA rats. Despite similar antiarthritic activity, the polymeric micellar formulation showed a reduction in the ratio of cardiotoxic-over-cardioprotective eicosanoids of ArA in the heart and plasma of AA rats. The results showed the positive effect of diclofenac prodrug nanodelivery in changing the normal biodistribution of diclofenac away from the heart, leading to lowered diclofenac-induced biomarkers of cardiotoxicity in the heart and plasma of AA rats.
中文翻译：
双氯芬酸的聚合物胶束配方可减少心脏暴露，可正常化CYP介导的佐剂关节炎大鼠模型中花生四烯酸失衡的代谢：对双氯芬酸通过纳米药物递送减少心血管副作用的影响。
在这项研究中，我们测试了心脏中药物存在的程度是否会导致非甾体类抗炎药（NSAIDs）的心血管风险升高。具有高心血管（CV）风险的NSAID（双氯芬酸）的荧光标记纳米制剂被开发为双氯芬酸乙酯（DFEE），封装在可追溯的（花青酸5.5标记）高分子胶束（DFEE-TM）中，基于甲氧基聚（环氧乙烷） -嵌段-聚（ε-己内酯）（PEO-b-PCL）（MW，5000：3500 g / mol）。在单次静脉内（iv）剂量的DFEE-TM给药后，比较了健康大鼠和佐剂性关节炎（AA）大鼠的双氯芬酸药代动力学和组织分布，以及器官和全身的离体近红外图像。此外，将DFEE-TM的生物分布和抗关节炎活性与游离双氯芬酸（每天一次腹膜内，腹膜内，10 mg / kg连续7天）进行比较。测定了心脏，肾脏和血浆中花生四烯酸（ArA）的细胞色素P450介导的心脏毒性（20-羟基二十碳四烯酸）与心脏保护性（环氧二十碳三烯酸）代谢产物的浓度比。在机管局的关节中发现了纳米载体，但在健康大鼠的关节中却没有。游离双氯芬酸和DFEE-TM都可控制AA。通过PEO-b-PCL胶束递送双氯芬酸减少了AA大鼠心脏中双氯芬酸的积累。尽管有类似的抗关节炎活性，聚合物胶束制剂显示，AA大鼠心脏和血浆中ArA的心脏毒性/心脏保护类二十烷酸比率降低。结果显示，双氯芬酸前药纳米递送对改变双氯芬酸远离心脏的正常生物分布具有积极作用，从而降低了双氯芬酸诱导的AA大鼠心脏和血浆中的心脏毒性生物标志物。
更新日期：2020-02-05
中文翻译：
双氯芬酸的聚合物胶束配方可减少心脏暴露，可正常化CYP介导的佐剂关节炎大鼠模型中花生四烯酸失衡的代谢：对双氯芬酸通过纳米药物递送减少心血管副作用的影响。
在这项研究中，我们测试了心脏中药物存在的程度是否会导致非甾体类抗炎药（NSAIDs）的心血管风险升高。具有高心血管（CV）风险的NSAID（双氯芬酸）的荧光标记纳米制剂被开发为双氯芬酸乙酯（DFEE），封装在可追溯的（花青酸5.5标记）高分子胶束（DFEE-TM）中，基于甲氧基聚（环氧乙烷） -嵌段-聚（ε-己内酯）（PEO-b-PCL）（MW，5000：3500 g / mol）。在单次静脉内（iv）剂量的DFEE-TM给药后，比较了健康大鼠和佐剂性关节炎（AA）大鼠的双氯芬酸药代动力学和组织分布，以及器官和全身的离体近红外图像。此外，将DFEE-TM的生物分布和抗关节炎活性与游离双氯芬酸（每天一次腹膜内，腹膜内，10 mg / kg连续7天）进行比较。测定了心脏，肾脏和血浆中花生四烯酸（ArA）的细胞色素P450介导的心脏毒性（20-羟基二十碳四烯酸）与心脏保护性（环氧二十碳三烯酸）代谢产物的浓度比。在机管局的关节中发现了纳米载体，但在健康大鼠的关节中却没有。游离双氯芬酸和DFEE-TM都可控制AA。通过PEO-b-PCL胶束递送双氯芬酸减少了AA大鼠心脏中双氯芬酸的积累。尽管有类似的抗关节炎活性，聚合物胶束制剂显示，AA大鼠心脏和血浆中ArA的心脏毒性/心脏保护类二十烷酸比率降低。结果显示，双氯芬酸前药纳米递送对改变双氯芬酸远离心脏的正常生物分布具有积极作用，从而降低了双氯芬酸诱导的AA大鼠心脏和血浆中的心脏毒性生物标志物。
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