Nintedanib esylate

Nintedanib esylate, as a kinase inhibitor, used for the treatment of non-small cell lung cancer suffered from first-pass metabolism which resulted in low oral bioavailability (~ 4.7%)^[1]. Nintedanib is an effective inhibitor of multityrosine kinase receptors.

In vitro, treatment with 1-4 µM nintedanib in a dose-dependently manner in Keloid fibroblasts inhibited cell proliferation, induced G0/G1 cell cycle arrest, and suppressed migration and invasion of keloid fibroblasts^[2]. In vitro test it shown that at 1 µM Nintedanib and 2.5 mM Pirfenidone decreased fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells^[3]. In vitro, 0.01-1.0 µM nintedanib in IPF (Idiopathic pulmonary fibrosis) fibroblasts decreased the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III^[4].

In vivo efficacy test it exhibited that treatment with 5 mg/mL nintedanib in eye drops four times daily, the outgrowths of blood and lymphatic vessels were obviously inhibited compared with the controls^[5]. In vivo, treatment with 3 µM and 5 µM nintedanib in mice up-regulated SP-D (Pulmonary surfactant protein D) messenger RNA expression^[6]. In vivo experiment it demonstrated that treatment with nintedanib (50, 100 mg/kg) orally could obviously recover the experimental colitis-related symptoms of mice caused by DSS, such as weight loss, increased DAI, shortened colon length, and colonic tissue injury^[7].

Kala SG, et al. Bioavailability enhancement of vitamin E TPGS liposomes of nintedanib esylate: formulation optimization, cytotoxicity and pharmacokinetic studies. Drug Deliv Transl Res. 2022 Nov;12(11):2856-2864.

Zhou BY, et al. Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization. Acta Pharmacol Sin. 2020 Sep;41(9):1234-1245.

Lehmann M, et al. Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis. Respir Res. 2018 Sep 15;19(1):175.

KnÜppel L, et al. A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly. Am J Respir Cell Mol Biol. 2017 Jul;57(1):77-90.

Lin T, et al. Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib. Drug Des Devel Ther. 2017 Apr 5;11:1147-1158.

Kamio K, et al. Nintedanib modulates surfactant protein-D expression in A549 human lung epithelial cells via the c-Jun N-terminal kinase-activator protein-1 pathway. Pulm Pharmacol Ther. 2015 Jun;32:29-36.

Li H, et al. Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways. Front Pharmacol. 2022 Jul 14;13:904420.

References:

Nintedanib esylate，作为一种激酶抑制剂，用于治疗非小细胞肺癌，首过代谢导致口服生物利用度低（~4.7%）^[1]。 Nintedanib 是一种有效的多酪氨酸激酶受体抑制剂。

在体外，1-4 77777#8181;M nintedanib 以剂量依赖性方式治疗瘢痕疙瘩成纤维细胞，抑制细胞增殖，诱导 G0/G1 细胞周期停滞，并抑制瘢痕疙瘩成纤维细胞的迁移和侵袭^[2]。体外试验表明，在 1 µM Nintedanib 和 2.5 mM Pirfenidone 下，小鼠和人类 3D-LTC 以及 pmATII 细胞^[3] 中的纤维化基因表达（包括胶原蛋白 1a1 和纤连蛋白）降低。在体外，0.01-1.0 µM nintedanib 在 IPF（特发性肺纤维化）成纤维细胞中降低胶原蛋白 I 和 V、纤连蛋白和 FKBP10 的表达，并减弱胶原蛋白 I 和 III 的分泌^[4] .

体内药效试验表明，5mg/mL尼达尼布滴眼液每天4次治疗，与对照组相比，血管和淋巴管的增生明显受到抑制^{[5]。在体内，用 3 µM 和 5 µM 尼达尼布治疗小鼠可上调 SP-D（肺表面活性蛋白 D）信使 RNA 表达[6]。体内实验表明，口服尼达尼布（50、100 mg/kg）可明显恢复DSS引起的小鼠实验性结肠炎相关症状，如体重减轻、DAI增加、结肠长度缩短、结肠组织损伤< sup>[7]}.

Kala SG, et al.尼达尼布乙磺酸盐维生素 E TPGS 脂质体的生物利用度增强:配方优化、细胞毒性和药代动力学研究。 Drug Deliv Transl Res. 2022 年 11 月；12(11):2856-2864。

Zhou BY, et al. Nintedanib 通过阻断多种激酶的磷酸化和增强受体内化来抑制瘢痕疙瘩成纤维细胞的功能。 Acta Pharmacol 罪。 2020 年 9 月；41(9):1234-1245。

Lehmann M 等人。尼达尼布和吡非尼酮对肺纤维化离体小鼠和人肺组织培养物中肺泡上皮细胞功能的不同影响。呼吸研究。 2018 年 9 月 15 日；19(1):175。

KnÜppel L, et al.尼达尼布和吡非尼酮的新型抗纤维化机制。抑制胶原原纤维组装。 Am J Respir Cell Mol Biol。 2017 年 7 月；57(1):77-90。

Lin T, et al.多激酶抑制剂尼达尼布在体外和体内抑制淋巴管生成。药物 Devel Ther。 2017 年 4 月 5 日；11:1147-1158。

Kamio K 等人。 Nintedanib 通过 c-Jun N-末端激酶-激活蛋白-1 通路调节 A549 人肺上皮细胞中表面活性蛋白-D 的表达。 Pulm Pharmacol Ther。 2015 年 6 月；32:29-36。

Li H, et al. Nintedanib 通过抑制 CEBPB/PCK1 和 CEBPB/EFNA1 通路减轻实验性结肠炎。前药理学。 2022 年 7 月 14 日；13:904420。