PPARδ (EC50 = 1.06 μM); PPARγ (EC50 = 1.47 μM); PPARα (EC50 = 22.4 μM); COX-2 (IC50 = 48 μM)

fenofibric Acid 是一种 PPAR 激活剂，其 PPARα、PPARγ 和 PPARδ 的 EC50 值分别为 22.4 µM、1.47 µM 和 1.06 µM[1]。 fenofibric Acid（10、25、50、75 和 100 nM）剂量依赖性地抑制 COX-2 酶，IC50 为 48 nM [2]。在 HepG2 细胞中，500 nM 的非诺贝酸会降低 AOX1 蛋白的数量 [3]。浓度为 100 µM 时，非诺贝酸可抑制 JNK1/2、c-Jun 和 p38 MAPK 的磷酸化。此外，它还可以防止活性氧的积累、内质网应激和血视网膜屏障 (BRB) 的破坏。 ARPE-19 细胞表现出缺氧和高葡萄糖 (HG)。在暴露于缺氧和 HG 条件下的 ARPE-19 细胞中，非诺贝酸 (100 µM) 会触发 IGF-IR/Akt/ERK1/2 介导的生存信号通路 [4]。

Fenofibric Acid（1、5、10 mg/kg，口服）对 Wistar 大鼠中角叉菜胶诱导的急性炎症具有抗炎作用 [2]。

脂联素保护肝脏免受肥胖或酒精引起的脂肪变性，因此分析了脂联素对人肝细胞的影响。基因芯片实验表明，重组脂联素下调醛氧化酶1（AOX1）的表达，实时RT-PCR和免疫印迹证实了这一点。AOX1是一种异生物质代谢蛋白，产生活性氧（ROS），促进细胞损伤和纤维化。脂联素和非诺贝特酸激活过氧化物酶体增殖物激活受体α（PPARα），两者都抑制AOX1蛋白，这被PPARα拮抗剂RU486阻断。肥胖与低脂联素、肝脏PPARα活性降低和脂肪肝有关，与对照组相比，高脂肪饮食的大鼠肝脏中发现了AOX1。肥胖时升高的游离脂肪酸和瘦素在体外未能上调AOX1。目前的数据表明，脂联素通过激活PPARα来降低AOX1，而脂肪肝疾病与肝脏AOX1升高有关。高AOX1可能与较高的ROS有关，ROS被很好地描述为诱导肝组织纤维化，但也可能影响药物代谢和活性[3]。

---

使用常规分光光度法研究了抗高脂血症药物非诺贝特及其I期生物转化代谢产物非诺贝特在计算机和体外对COX-1（PDB ID:3N8Y）和COX-2（PDB ID:1PXX）的抑制潜力，以研究其对从sf21细胞中的杆状病毒表达系统分离的人重组COX-2酶的影响（EC 1.14.99.1）。受试化合物非诺贝特酸、非诺贝特和标准药物双氯芬酸对COX-2的结合能分别为-9.0、-7.2和-8.0 kcal mol-1，对COX-1的结合能则分别为-7.2、-7.0和-6.5 kcalmol-1。在体外研究中，两种受试化合物均抑制COX-2酶活性。非诺贝特的IC50值为48 nM，其次是非诺贝特（82 nM），而双氯芬酸的IC50值则为58 nM[2]。

在这项研究中，我们发现糖尿病患者视网膜色素上皮（RPE）中应激介导和存活信号之间存在不平衡，凋亡标志物升高。由于非诺贝特酸（FA）治疗可减少糖尿病视网膜病变（DR）的进展，我们研究了糖尿病环境的两个组成部分高血糖和缺氧对ARPE-19细胞（永生化人RPE细胞系）应激、凋亡和存活途径的影响，以及FA是否能够预防这些条件引起的有害影响。在高糖（HG）培养基中或缺氧（1%氧气）下培养的ARPE-19细胞诱导应激活化激酶JNK和p38 MAPK的磷酸化。这两种条件的结合增加了这种效果。同样，高血糖和缺氧引发内质网（ER）应激标志物PERK和eIF2α的磷酸化以及促凋亡转录因子CHOP的诱导。在这些实验条件下，活性氧（ROS）升高，紧密连接的完整性被破坏。相反，用FA处理的ARPE-19细胞受到保护，免受高血糖和缺氧引起的这些有害影响。FA增加了在高血糖和缺氧条件下培养的细胞中胰岛素样生长因子I受体（IGF-IR）介导的存活信号，从而抑制了半胱氨酸天冬氨酸蛋白酶-3的激活和BclxL的下调。此外，FA增加了自噬标志物LC3-II。总之，我们的研究结果表明，FA通过下调应激介导的信号传导和诱导自噬和存活途径，在RPE中引发双重保护作用。这些分子机制可能与临床试验中报道的非诺贝特的有益作用有关[4]。

Fenofibrate was screened for their anti-inflammatory potentials in vivo using carrageenan-induced paw oedema method in Wistar rats. Furthermore, under in vivo conditions in carrageenan-induced paw oedema rodent model, fenofibric acid exhibited relatively potent anti-inflammatory activity compared with fenofibrate. Hence, we conclude that fenofibric acid and fenofibrate are not only anti-hyperlipidemic but also shows potent anti-inflammatory activity, which may have an additional impact in the treatment of diabetic complications, viz., hyperlipidemia and inflammation leading to atherosclerosis[2].

Absorption, Distribution and Excretion
Some studies have demonstrated that the bioavailability of fenofibric acid (a sample administration of 130 mg oral suspension to healthy volunteers about 4 hours after a light breakfast) is approximately 81% in the stomach, 88% in the proximal small bowel, 84% in the distal small bowel, and 78% in the colon. Nevertheless, following the oral administration of fenofibric acid in healthy volunteers, median peak plasma levels for the drug occurred about 2.5 hours after administration. Moreover, exposure after administration of three 35 mg fenofibric acid tablets is largely comparable to that of one 105 mg tablet.
Fenofibric acid metabolites are largely excreted in the urine.
The volume of distribution for fenofibric acid is demonstrated to be 70.9 +/- 27.5 L.
In five elderly volunteers aged 77 to 87, the oral clearance of fenofibric acid after a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults.

---

Metabolism / Metabolites
In vitro and in vivo metabolism studies reveal that fenofibric acid does not experience significant oxidative metabolism via the cytochrome P450 isoenzymes. The CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzymes are not known to play a role in the metabolism of fenofibric acid. Rather, fenofibric acid is predominantly conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
Fenofibric Acid has known human metabolites that include Fenofibryl glucuronide.

---

Biological Half-Life
Following once daily dosing, fenofibric acid demonstrates an elimination associated with a half-life of about 20 hours after absorption.

Protein Binding
Fenofibric acid demonstrates serum protein binding of approximately 99% in ordinary and hyperlipidemic subjects.

[1]. Comparative molecular profiling of the PPARα/γ activator aleglitazar: PPAR selectivity, activity and interaction with cofactors. ChemMedChem. 2012 Jun;7(6):1101-11.

[2]. Anti-inflammatory activity of anti-hyperlipidemic drug, fenofibrate, and its phase-I metabolite fenofibric acid: in silico, in vitro, and in vivo studies. Inflammopharmacology. 2017 Dec 13.

[3]. Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. Biochem Biophys Res Commun. 2006 Nov 24;350(3):731-5. Epub 2006 Sep 27.

[4]. Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions. J Cell Physiol. 2012 Jun;227(6):2352-62.

Fenofibric acid is a monocarboxylic acid that is 2-methylpropanoic acid substituted by a 4-(4-chlorobenzoyl)phenoxy group at position 2. It is a metabolite of the drug fenofibrate. It has a role as a marine xenobiotic metabolite and a drug metabolite. It is a chlorobenzophenone, a monocarboxylic acid and an aromatic ketone.
Fenofibric acid is a lipid-lowering agent that is used in severe hypertriglyceridemia, primary hyperlipidemia, and mixed dyslipidemia. It works to decrease elevated low-density lipoprotein cholesterol, total cholesterol, triglycerides, apolipoprotein B, while increasing high-density lipoprotein cholesterol. Due to its high hydrophilicity and poor absorption profile, prodrug ,[fenofibrate], and other conjugated compounds of fenofibric acid, such as choline fenofibrate, have been developed for improved solubility, gastrointestinal absorption, and bioavailability, and more convenient administration.
Fenofibric acid is a Peroxisome Proliferator Receptor alpha Agonist.
Fenofibric Acid is the active form of fenofibrate, a synthetic phenoxy-isobutyric acid derivate with antihyperlipidemic activity.
See also: Fenofibrate (active moiety of); Choline Fenofibrate (active moiety of).

---

Drug Indication
For use as an adjunctive therapy to diet to: (a) reduce triglyceride levels in adult patients with severe hypertriglyceridemia, and (b) reduce elevated total cholesterol, low-density-lipoprotein (LDL-C), triglycerides, and apolipoprotein B, and to increase high-density-lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb).
FDA Label

---

Mechanism of Action
Having performed clinical studies with in vivo transgenic mice and in vitro human hepatocyte cultures, it is believed that the principal mechanism of action of fenofibric acid is demonstrated through its capability to activate peroxisome proliferator receptor alpha (PPAR-alpha). By activating PPAR-alpha, fenofibric acid increases lipolysis and the elimination of triglyceride-rich particles from plasma by actuating lipoprotein lipase and reducing production of apoprotein C-III, which acts as an inhibitor of lipoprotein lipase activity. The resultant decrease in triglycerides causes an alteration in the size and composition of low-density-lipoprotein from small, dense particles to large, buoyant ones. The size of these larger low-density-lipoprotein particles have a greater affinity for cholesterol receptors and are therefore catabolized more rapidly. Additionally, fenofibric acid's activation of PPAR-alpha also induces an increase in the synthesis of apoproteins apo A-I, apo A-II, and high-density-lipoprotein. Moreover, the use of fenofibric acid can also act to reduce serum uric acid levels in ordinary or hyperuricemic individuals by increasing the urinary excretion of uric acid.

---

Pharmacodynamics
Various clinical studies have shown that elevated levels of total cholesterol, low-desnsity-lipoprotein (LDL-C), and apolipoprotein B (apo B) - an LDL membrane complex - are associated with human atherosclerosis. Concurrently, decreased levels of high-density-lioprotein (HDL-C) and its transport complex, apolipoproteins apo AI and apo AII, are associated with the development of atherosclerosis. Furthermore, epidemiological investigations demonstrate that cardiovascular morbidity and mortality vary directly with the levels of total cholesterol, LDL-C, and triglycerides, and inversely with the level of HDL-C. Fenofibric acid, the active metabolite of fenofibrate, subsequently produces reductions in total cholesterol, LDL-C, apo B, total triglycerides, and triglyceride rich lipoprotein (VLDL) in treated patients. Moreover, such treatment with fenofibrate also results in increases in HDL-C and apo AI and apo AII.

C17H15O4CL

318.7516

318.065

C, 64.06; H, 4.74; Cl, 11.12; O, 20.08

42017-89-0

Choline Fenofibrate;856676-23-8;Fenofibric acid (Standard);42017-89-0;Fenofibric acid-d6;1092484-69-9

64929

White to off-white solid powder

1.3±0.1 g/cm3

486.5±35.0 °C at 760 mmHg

176--179ºC

248.0±25.9 °C

0.0±1.3 mmHg at 25°C

1.585

3.86

63.6

1

4

5

22

405

0

MQOBSOSZFYZQOK-UHFFFAOYSA-N

InChI=1S/C17H15ClO4/c1-17(2,16(20)21)22-14-9-5-12(6-10-14)15(19)11-3-7-13(18)8-4-11/h3-10H,1-2H3,(H,20,21)

2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid

Procetofenic acid; 2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropanoic acid; 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoic acid; Trilipix; alpha 1081; LF 178 acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 100 mg/mL (~313.73 mM)
H2O : ~1 mg/mL (~3.14 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.84 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.5 mg/mL (7.84 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。