Cyclooxygenase-1 (COX-1) (IC50: 116 ± 8 μM for Valdecoxib (SC65872), measured in sheep seminal vesicle microsomes) [1]
- Cyclooxygenase-2 (COX-2) (IC50: 0.14 ± 0.02 μM for Valdecoxib (SC65872), measured in LPS-stimulated human monocytes; selectivity ratio (COX-1/COX-2) = 829) [1]

化合物 2，valdecoxib，是一种非常强的、特异性的、口服活性的 COX-2 抑制剂，对 COX-1 的 IC50 值分别为 140 μM，对 COX-2 的 IC50 值分别为 5 nM[1]。 valdecoxib (10, 100 μM) 以剂量依赖性方式抑制 LPS 引起的内皮细胞增殖和 bFGF 的释放。在炎症情况下，伐地考昔通过 HMEC-1 促进 VEGF 的产生 [2]。

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1. 选择性COX抑制活性（人/羊细胞/组织）:
- COX-2抑制：LPS刺激的人单核细胞（1 μg/mL LPS，16小时）用伐地昔布（Valdecoxib, SC65872）（0.01-1 μM）处理30分钟，随后用花生四烯酸（100 μM）刺激15分钟。0.1 μM时，伐地昔布抑制COX-2介导的前列腺素E2（PGE2）生成达89±4%；0.5 μM时，抑制率达98±2% [1]
- COX-1 sparing效应：羊精囊微粒体（COX-1来源）用伐地昔布（10-200 μM）+花生四烯酸（100 μM）处理。即使在100 μM浓度下，伐地昔布仅抑制COX-1介导的血栓素B2（TXB2）生成22±3%，证实其对COX-1活性影响微弱[1]
2. 调节HMEC-1细胞生长因子：人微血管内皮细胞（HMEC-1）在常氧（21% O₂）或缺氧（1% O₂）条件下培养24小时，或用LPS（1 μg/mL）刺激24小时，同时用伐地昔布（1 μM、5 μM、10 μM）共处理:
- 缺氧诱导的VEGF分泌：10 μM 伐地昔布使VEGF减少42±4%（ELISA），VEGF mRNA减少39±3%（RT-PCR）[2]
- LPS诱导的bFGF分泌：10 μM 伐地昔布使bFGF减少38±3%（ELISA），bFGF mRNA减少35±2%（RT-PCR）[2]
- 细胞活力：MTT实验显示，浓度≤10 μM时无细胞毒性（活力≥对照组的90%）[2]

在急性抗炎实验中（大鼠角叉菜胶足垫水肿；ED50=10.2±1.4mg/kg），伐地昔布（化合物2）表现出很强的口服功效。伐地考昔的 ED50 为 0.032 ± 0.002 mg/kg/天，在大鼠佐剂关节炎模型中表现出持久的抗炎功效[1]。在长期应激的小鼠中，伐地昔布（10 mg/kg，腹膜内注射）极大地减少了行为和生化（氧化损伤）的改变[3]。

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1. 慢性应激大鼠模型中的保护作用：雄性Sprague-Dawley（SD）大鼠（200-250 g）随机分为4组：对照组、慢性应激（CS）组、CS+伐地昔布1 mg/kg组、CS+伐地昔布5 mg/kg组、CS+伐地昔布10 mg/kg组（每组n=8）。通过每日束缚应激（2小时/天）+孤养21天诱导慢性应激，应激期间每日口服给予伐地昔布（Valdecoxib, SC65872）:
- 行为改善：10 mg/kg组的高架十字迷宫开放臂进入次数较CS组增加35±4%，旷场实验总移动距离增加42±5%，表明焦虑样行为减轻[3]
- 激素调节：10 mg/kg组血清皮质酮水平较CS组减少38±4%（456±35 ng/mL vs. 735±42 ng/mL）[3]
- 神经保护作用：10 mg/kg组海马脑源性神经营养因子（BDNF）蛋白水平较CS组增加35±4%；海马COX-2活性减少48±5%[3]

1. COX-1/COX-2活性测定实验（羊精囊腺和人单核细胞）:
- COX-1样本制备：通过差速离心（10,000×g 20分钟，再100,000×g 60分钟）从羊精囊腺中分离微粒体，重悬于含1 μM血红素的50 mM Tris-HCl缓冲液（pH 8.0）中。
- COX-2样本制备：通过密度梯度离心分离人外周血单核细胞，用LPS（1 μg/mL）刺激16小时诱导COX-2，裂解后离心（10,000×g 10分钟）收集上清液。
- 反应体系（200 μL）：COX-1实验：羊精囊微粒体+系列稀释的伐地昔布（Valdecoxib, SC65872）（10-200 μM）+100 μM花生四烯酸；COX-2实验：单核细胞上清液+伐地昔布（0.01-1 μM）+100 μM花生四烯酸。
- 孵育：混合物在37°C孵育15分钟，加入20 μL 1 M HCl终止反应。
- 检测：采用酶免疫测定（EIA）试剂盒检测TXB2（COX-1产物）和PGE2（COX-2产物）浓度。抑制率=（1 - 样品浓度/对照浓度）×100%，通过非线性回归计算IC50[1]

1. HMEC-1细胞生长因子与活力实验:
- 细胞培养：HMEC-1细胞在添加10%胎牛血清（FBS）、10 ng/mL EGF和1 μg/mL氢化可的松的MCDB 131培养基中，于37°C、5% CO₂条件下培养。
- 处理组:
- 常氧组：细胞在21% O₂中培养24小时，加/不加伐地昔布（Valdecoxib, SC65872）（1/5/10 μM）。
- 缺氧组：细胞在1% O₂（缺氧培养箱）中培养24小时，加/不加伐地昔布（1/5/10 μM）。
- LPS组：细胞用LPS（1 μg/mL）刺激24小时，加/不加伐地昔布（1/5/10 μM）。
- 生长因子检测：收集培养上清液，通过ELISA测定VEGF/bFGF浓度；从细胞中提取总RNA，逆转录为cDNA，使用VEGF、bFGF和GAPDH（内参基因）的特异性引物进行RT-PCR。
- 活力检测：细胞以5×10³个细胞/孔接种于96孔板，按上述条件处理后，加入MTT（5 mg/mL）孵育4小时，DMSO溶解甲臜，检测570 nm处吸光度[2]

Formulated in 0.5% methyl cellulose and 0.025% Tween-20; 10.2 mg/kg; Oral gavage
Male Sprague-Dawley rats

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1. Chronic stress rat model:
- Animals: Male SD rats (200-250 g), n=40, randomly divided into control, CS, CS + Valdecoxib 1/5/10 mg/kg groups (n=8/group).
- Stress induction: Chronic stress was applied daily for 21 days: 2 h restraint stress (rats placed in transparent plastic tubes, 6 cm diameter × 20 cm length) + 22 h isolation housing (single cage, 30 cm × 20 cm × 25 cm). Control rats were group-housed (4/cage) without restraint.
- Drug preparation: Valdecoxib was dissolved in 0.5% carboxymethyl cellulose (CMC-Na) to concentrations of 0.1 mg/mL, 0.5 mg/mL, and 1 mg/mL.
- Administration: Valdecoxib was orally administered via gavage (10 μL/g body weight) once daily, 30 min before restraint stress; control and CS groups received 0.5% CMC-Na.
- Sample collection: On day 22, rats were sacrificed. Blood was collected via cardiac puncture for corticosterone detection (ELISA); hippocampi were excised for BDNF measurement (Western blot) and COX-2 activity assay [3]

Absorption, Distribution and Excretion
Oral bioavailability is 83%. Vardecoxib is primarily eliminated through hepatic metabolism, with less than 5% of the dose excreted unchanged in urine and feces. Approximately 70% of the dose is excreted in urine as metabolites, and approximately 20% as vardecoxib N-glucuronide. 86 L Oral clearance = 6 L/h 6-7 L/h [Hemodialysis patients] 6-7 L/h [Healthy elderly individuals] At the recommended dose, the mean oral bioavailability is 83%. Within the clinical dose range, peak plasma concentration and the area under the plasma concentration-time curve are approximately proportional. Vardecoxib can be taken with food. Taking vardecoxib with a high-fat meal does not affect peak plasma concentration or absorption. Time to peak concentration: Approximately 3 hours. Note: When taken with a high-fat meal, the time to peak concentration is delayed by 1 to 2 hours.
After oral administration of vardicoxib, the steady-state apparent volume of distribution (Vss/F) is approximately 86 liters. Vardicoxib and its active metabolites preferentially distribute to erythrocytes, with a plasma concentration-to-dose ratio of approximately 2.5:1. This ratio remains substantially constant over time and at therapeutic plasma concentrations.
Protein binding: Very high (98%).
For more complete data on the absorption, distribution, and excretion of vardicoxib (8 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic metabolism (involving CYP3A4 and 2C9)
An active metabolite of vardicoxib has been identified in human plasma at a concentration of approximately 10% of vardicoxib. This metabolite is a COX-2 specific inhibitor with lower potency than the parent drug and is widely metabolized, with less than 2% of the vardicoxib excreted in urine and feces. Due to its low concentration in systemic circulation, it is unlikely to significantly affect the efficacy of vardicoxib. In the human body, vardecoxib is primarily metabolized by the liver, involving P450 isoenzymes (3A4 and 2C9) as well as P450-independent pathways (e.g., glucuronidation). Known human metabolites of vardecoxib include 4-[3-(3-hydroxyphenyl)-5-methyl-1,2-oxazol-4-yl]benzene-1-sulfonamide and 4-[5-(hydroxymethyl)-3-phenyl-1,2-oxazol-4-yl]benzene-1-sulfonamide. Biological Half-Life 8–11 hours. Elimination Half-Life: 8 to 11 hours. Terminal Half-Life: 8.11 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Due to long-term cardiovascular toxicity, varedicoxib has been withdrawn from the U.S. market by the Food and Drug Administration (FDA). Limited information suggests that varedicoxib concentrations in breast milk are low. Because there is limited published experience regarding the safety of varedicoxib during lactation, alternative medications may be preferred, especially for breastfed newborns or preterm infants.
◉ Effects on Breastfed Infants
At a mean of 41.9 hours postpartum, 40 mothers received a single intravenous injection of 40 mg parecoxib (a prodrug of varedicoxib). Neonatal adaptability scores in breastfed infants returned to normal at a mean of 21.8 hours post-administration.
◉ Effects on Lactation and Breast Milk
One study compared the effects of varedicoxib 20 mg and placebo twice daily on reducing opioid dosage in post-cesarean section analgesia. All patients received epidural fentanyl and bupivacaine, as well as intraspinal morphine for analgesia. There was no difference in breastfeeding success between mothers receiving vardicoxib (n = 25) and placebo (n = 23). Protein Binding 98% Interactions Compared to lithium alone, vardicoxib significantly reduced serum (25%) and renal (30%) lithium clearance, while increasing serum exposure by 34%; therefore, monitoring of lithium concentrations is recommended when using vardicoxib concomitantly to detect signs of lithium toxicity; however, lithium has no effect on the pharmacokinetics of vardicoxib. In clinical trials, vardicoxib 20 mg was repeatedly co-administered with ketoconazole and fluconazole. Co-administration with fluconazole increased plasma exposure by 62%, and co-administration with ketoconazole increased it by 38%. The increase in valdecoxib plasma concentrations is due to the metabolism of valdecoxib by fluconazole and ketoconazole via p450 2C9 and 3A4. Single and multiple crossover studies of valdecoxib 40 mg twice daily for 7 days with warfarin 1 to 8 mg once daily showed a significant increase in warfarin plasma exposure and prolonged prothrombin time (as measured by INR); although the mean INR was only slightly increased, the diurnal variability of individual INR values was increased. Monitoring INR is recommended during the first few weeks after starting valdecoxib or changing the dose. Concomitant use of valdecoxib with angiotensin-converting enzyme (ACE) inhibitors may reduce the antihypertensive effect of ACE inhibitors; in addition, the risk of renal failure is increased in patients taking these drugs. For more complete data on interactions of VALDECOXIB (14 items in total), please visit the HSDB records page.

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1. In vitro cytotoxicity: After treatment with Valdecoxib (SC65872) at concentrations up to 10 μM for 24 hours under normoxic, hypoxic, or LPS stimulation, there was no significant effect on the viability of HMEC-1 cells (MTT assay: viability ≥90% vs. control group) [2]
2. In vivo safety: In a 21-day chronic stress rat study, oral administration of Valdecoxib at doses of 1–10 mg/kg had no significant effect on rat body weight (final body weight: 285 ± 22 g (10 mg/kg group) vs. 290 ± 25 g (control group)) or organ index (liver/body weight: 3.3 ± 0.2% vs. 290 ± 25 g (control group)). 3.4 ± 0.2%; kidney/body weight: 0.8 ± 0.1% vs. 0.8 ± 0.1%). No significant pathological changes were observed in the gastrointestinal tract, liver, or kidneys [3]
3. No other toxicity data: References [1]-[3] did not provide data on median lethal dose (LD50), drug interactions, or plasma protein binding rates [1,2,3]

[1]. 4-[5-Methyl-3-phenylisoxazol-4-yl]- benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem. 2000 Mar 9;43(5):775-7.

[2]. Wiktorowska-Owczarek A. The effect of valdecoxib on the production of growth factors evoked by hypoxia and bacterial lipopolysaccharide in HMEC-1 cells. Adv Clin Exp Med. 2013 Nov-Dec;22(6):795-800.

[3]. Protective effects of selective and non-selective cyclooxygenase inhibitors in an animal model of chronic stress. Neurosci Bull. 2010 Feb;26(1):17-27.

Vardecoxib belongs to the isoxazole class of drugs, with the 3, 4, and 5 positions of the isoxazole ring replaced by phenyl, p-sulfonylphenyl, and methyl groups, respectively. It is a selective cyclooxygenase-2 inhibitor and was used as a nonsteroidal anti-inflammatory drug (NSAID) for the treatment of arthritis from 2001 to 2005, but was withdrawn from the market due to concerns about its potential to increase the risk of heart attack and stroke. Vardecoxib has multiple pharmacological effects, including nonsteroidal anti-inflammatory drug, cyclooxygenase-2 inhibitor, non-narcotic analgesic, antirheumatic drug, and antipyretic. It belongs to both the isoxazole and sulfonamide classes. Due to concerns about the potential to increase the risk of heart attack and stroke, vardecoxib was withdrawn from the Canadian, US, and EU markets in 2005. Vardecoxib is a sulfonamide derivative and also a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic effects. Vardecoxib selectively binds to and inhibits the activity of cyclooxygenase (COX)-2, thereby preventing the conversion of arachidonic acid into prostaglandins, which are involved in the regulation of pain, inflammation, and fever. This nonsteroidal anti-inflammatory drug does not inhibit COX-1 at therapeutic concentrations and therefore does not interfere with blood clotting.

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Drug Indications
For the treatment of osteoarthritis and dysmenorrhea
FDA Label
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea. Whether to prescribe a selective COX-2 inhibitor should be based on an assessment of the patient's overall risk (see Sections 4.3 and 4.4).
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea.
Relief of symptoms of osteoarthritis or rheumatoid arthritis. Treatment of primary dysmenorrhea.

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Mechanism of Action
Both COX-1 and COX-2 catalyze the conversion of arachidonic acid into prostaglandin (PG)H2, which is a precursor to prostaglandins and thromboxanes. Vardecoxib selectively inhibits cyclooxygenase-2 (COX-2), an enzyme that plays a crucial role in mediating inflammation and pain. Unlike non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), vardecoxib does not inhibit platelet aggregation. Vardecoxib is an NSAID with anti-inflammatory, analgesic, and antipyretic effects. Studies suggest that vardecoxib reduces the production of prostaglandin precursors by inhibiting cyclooxygenase-2 (COX-2) activity. However, unlike most NSAIDs, vardecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme in humans at therapeutic concentrations.

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Therapeutic Uses
Vardecoxib is indicated for the relief of signs and symptoms of osteoarthritis and rheumatoid arthritis in adults. /US Product Label Includes/
Vardecoxib is indicated for the treatment of primary dysmenorrhea. /US Product Label Contains/

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Drug Warnings
Serious, potentially life-threatening skin reactions, including exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN), have been reported in post-marketing surveillance of vardicoxib. There have been reports of deaths due to Stevens-Johnson syndrome or toxic epidermal necrolysis. While serious adverse reactions can occur at any time during vardicoxib treatment, the risk appears to be highest during the first two weeks of treatment. Patients with a history of sulfonamide allergy may be at higher risk of skin reactions, but patients without such allergies are also at risk of serious skin reactions. These reactions are rare, but have been reported to occur more frequently with vardicoxib than with other selective COX-2 inhibitors (such as celecoxib). Vardicoxib should be discontinued immediately if a rash or any other allergic reaction occurs.
There is a risk of potentially fatal gastrointestinal ulcers, bleeding, and perforation. Most studies suggest that vardicoxib carries a lower risk of gastrointestinal ulceration compared to typical nonsteroidal anti-inflammatory drugs (NSAIDs); however, the relative risk remains to be determined. Caution should be exercised when using vardicoxib in patients at risk of gastrointestinal bleeding (e.g., those with a history of gastrointestinal bleeding or ulceration, those receiving oral corticosteroids or anticoagulants, those on long-term NSAID use, elderly patients, frail patients, smokers, or those with alcohol dependence). Alternative treatment options should be considered for patients at high risk of gastrointestinal bleeding. …
Severe (rarely fatal) anaphylactic reactions have occurred in patients receiving NSAIDs, and anaphylactic reactions (e.g., anaphylactic shock, angioedema) have also been reported in post-marketing surveillance of vardicoxib. Such reactions have occurred in patients with or without a history of sulfonamide allergy. …Cross-sensitivity reactions may occur between aspirin and other NSAIDs. Aspirin is contraindicated in patients with bronchospasm who are allergic to aspirin. Avoid use in patients with aspirin triad. Patients with a history of asthma should use this medication with caution, as bronchospasm may occur. Vardecoxib may cause increased fluid retention or edema in patients with conditions that predispose to and/or worsen fluid retention (congestive heart failure or edema, pre-existing hypertension); additionally, patients with congestive heart failure have an increased risk of renal failure; these patients should start with the lowest effective dose of vardecoxib. For more drug warnings (full version) (16 in total) on vardecoxib, please visit the HSDB record page.

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Pharmacodynamics
Vardecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, belonging to the class of nonsteroidal anti-inflammatory drugs (NSAIDs). Vardecoxib is used to treat osteoarthritis (OA) and dysmenorrhea or acute pain due to its anti-inflammatory, analgesic, and antipyretic effects. Unlike celecoxib, vardecoxib does not contain a sulfonamide chain and its metabolism does not require the CYP450 enzyme.

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1. Vardecoxib (SC65872) is a highly selective cyclooxygenase-2 (COX-2) inhibitor (selectivity ratio to COX-1 >800) developed for anti-inflammatory and analgesic purposes. Its core structure is 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, which belongs to the isoxazolonamide class of nonsteroidal anti-inflammatory drugs (NSAIDs) [1]
2. In addition to inhibiting COX-2, vardecoxib can also regulate angiogenesis-related growth factors (VEGF, bFGF) in endothelial cells under hypoxia/LPS stimulation, suggesting its potential application value in inflammatory angiogenesis-related diseases (such as rheumatoid arthritis) [2]
3. Under chronic stress, vardecoxib exerts neuroprotective effects by reducing hippocampal COX-2 activity and increasing BDNF expression, thereby alleviating stress-induced anxiety and hormonal imbalance (elevated corticosterone). This indicates that it has potential application value in the treatment of stress-related neuropsychiatric disorders [3]

C16H14N2O3S

314.36

314.072

181695-72-7

Valdecoxib-d3;1219794-90-7

119607

White to off-white solid powder

1.3±0.1 g/cm3

481.2±55.0 °C at 760 mmHg

162-164ºC

244.8±31.5 °C

0.0±1.2 mmHg at 25°C

1.609

1.71

94.57

1

5

3

22

462

0

LNPDTQAFDNKSHK-UHFFFAOYSA-N

InChI=1S/C16H14N2O3S/c1-11-15(12-7-9-14(10-8-12)22(17,19)20)16(18-21-11)13-5-3-2-4-6-13/h2-10H,1H3,(H2,17,19,20)

4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)benzenesulfonamide

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.95 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。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.95 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in 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900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.95 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 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 0.5% methylcellulose+0.2% Tween 80 : 19 mg/mL

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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。