HMG-CoA reductase [IC50 = 5.6 μM.]

普伐他汀 (CS-514) 是一种他汀类药物，与饮食、运动和减肥相结合，可降低胆固醇并预防心血管疾病[1]。

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普伐他汀钠是普伐他汀的钠盐，具有降低胆固醇和潜在的抗肿瘤活性。普伐他汀竞争性抑制肝羟甲基戊二酰辅酶A （HMG-CoA）还原酶，该酶催化HMG-CoA转化为甲羟戊二酸，这是胆固醇合成的关键步骤。该药物降低血浆胆固醇和脂蛋白水平，并通过抑制干扰素γ刺激的抗原呈递细胞（如人血管内皮细胞）上的MHC II（主要组织相容性复合体II）来调节免疫反应。此外，普伐他汀和其他他汀类药物一样，在多种肿瘤细胞中表现出促凋亡、生长抑制和促分化活性；这些抗肿瘤活性可能部分是由于抑制Ras和Rho gtpase的异戊二烯化以及相关的信号级联反应。

普伐他汀（40 毫克，单剂量）可使健康受试者中人单核细胞来源的巨噬细胞的胆固醇合成减少 62%，使高胆固醇血症患者减少 47%。普伐他汀（40 毫克/天，8 周）可抑制高胆固醇血症患者的胆固醇合成 55%，并使 LDL 降解增加 57%。普伐他汀 (30 mg/kg/d) 可使接受照射的雄性 Wistar 大鼠营养不良病变长度缩短 34%，肌肉结构恢复，与 CCN2 水平降低相关。

血浆脂质过氧化水平的测定[2]
脂质过氧化产物采用硫代巴比妥酸（TBA）反应物质（TBARS）法，检测脂质过氧化的主要产物丙二醛（MDA）水平。简单地说，将100µL血浆加入试管中，与100µL蒸馏水、50µL 8.1%十二烷基硫酸钠（SDS）、375µL 20%乙酸和375µL 0.8% TBA在95°C水浴中孵育1小时。然后，将样品以4000 rpm离心10 min。将TBA加入样品中，立即得到比色反应，如前所述，通过532 nm波长测量。血浆MDA水平以nmol/mL表示。

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血浆抗氧化能力的测定[2]
如前所述，测定血浆的Trolox等效抗氧化能力（TEAC）。简单地说，用100 μg Trolox（6-羟-2,5,7,8-四甲基铬-2-羧酸）在1 mL醋酸钠缓冲液（0.4 M, C2H3NaO2.3H2O）和冰醋酸（0.4 M）中建立标准曲线，将血浆样品（20 μL）加入醋酸钠缓冲液和冰醋酸（200 μL）溶液中，在660 nm处读取吸光度。然后，用20 μL醋酸钠缓冲液（0.03 M）和冰醋酸（0.03 M）溶液（H2O2）和ABTS(2,2′-氮基-双（3-乙基苯-噻唑啉-6磺酸）；将Sigma， St. Louis， MO， USA)加入到样品中并孵育5分钟。然后，在分光光度计中进行第二次读取（660 nm）。用第一次读数的值减去第二次读数的值，样品的抗氧化活性用mmol Trolox当量/L表示。

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MMP-2酶谱分析[2]
如前所述，明胶酶谱法在胎盘中进行。简单地说，胎盘样品是用RIPA缓冲液（1 mM 1,10-邻菲罗啉，1 mM苯甲磺酰氟）和1 mM n -乙基马来酰亚胺制备的；含有蛋白酶抑制剂（4-（2-氨基乙基）苯磺酰氟（AEBSF）， E-64，贝司他汀，白细胞介素，抑蛋白蛋白和EDTA）。样品均质，用Bradford法测定蛋白质浓度。采用12%丙烯酰胺凝胶与明胶（0.05%）共聚，5μg胎盘蛋白电泳分离蛋白。在Triton X-100（2%）溶液中，在室温下洗涤两次，洗涤30分钟，在Tris-HCl缓冲液中孵育18小时，缓冲液中含有10 mmol/L CaCl2， pH为7.4。用考马斯亮蓝G-250对凝胶染色，用甲醇溶液对未染色的凝胶染色。采用ImageJ软件测定明胶水解活性。

血管反应性[2]
解剖腹主动脉段，切成4个环（3mm），其中2个环机械去除内皮，2个环保留内皮。每个主动脉环挂在两个钢丝钩之间，放入含有Krebs-Henseleit溶液(NaCl 130；氯化钾4.7;氯化钙1.6;KH2PO4 1.2;MgSO4 1.2;NaHCO3 15;葡萄糖11.1;（mmol/L）在pH 7.4和37℃条件下，用95% O2和5% CO2起泡，然后在1.5 g的基张力下稳定。[2]
在主动脉环平衡后，通过给药KCl （96 mM）获得KCl最大收缩量，以检测主动脉活力。为了检测内皮功能，用10−6 M的苯肾上腺素（Phe）预收缩主动脉环，并增加浓度（10−9至10−4 M）的乙酰胆碱（ACh）。为了证实内皮源性no依赖性血管舒张的参与，在与Phe预收缩的主动脉环中，在n ω-硝基- l -精氨酸甲酯（L-NAME, 3 × 10−4 M）存在的情况下，获得了对ACh的浓度响应曲线。对得到的浓度-效应曲线进行非线性回归（变斜率），得到了Rmax（最大反应）和pEC50（引起最大反应50%的浓度的负对数）。松弛曲线用松弛对ph诱导收缩的百分比表示，如前所述。[2]

Female Wistar rats were were allocated in cages with a 12 h light/dark cycle and controlled temperature (23 ± 2 °C), with access to food and water ad libitum. For mating overnight, the animals were kept in cages in the ratio of two females to one male in late afternoon. The following day, the detection of sperm and estrus cells in a vaginal smear confirmed the first day of gestation, and pregnant rats were distributed into four experimental groups:[2]
1. Normotensive Pregnant rats (Norm-Preg group): saline (0.9% NaCl) solution (0.3–0.45 mL) was intraperitoneally (i.p.) administered on days 1, 7, and 14, and saline was administered by gavage from pregnancy day 10 until 19 (n = 8).[2]
2. Normotensive pregnant rats treated with pravastatin (Norm-Preg + Prava group): saline was i.p. administered on days 1, 7, and 14, and pravastatin (10 mg/kg/day) was administrated by gavage from pregnancy day 10 until 19 (n = 8).[2]
3. Hypertensive pregnant rats (HTN-Preg group): hypertension was induced by i.p. administration of 12.5 mg of DOCA on the first day of pregnancy, followed by i.p. injection of 6.5 mg of DOCA on days 7 and 14 of pregnancy; drinking water was replaced by saline from pregnancy day 1 until 19; and saline was administered by gavage from pregnancy day 10 until 19 (n = 8).[2]
4. Hypertensive pregnant rats treated with pravastatin (HTN-Preg + Prava group): hypertension was induced by i.p. administration of 12.5 mg of DOCA on the first day of pregnancy, followed by i.p. injection of 6.5 mg of DOCA on days 7 and 14 of pregnancy; drinking water was replaced by saline from pregnancy day 1 until 19; and pravastatin (10 mg/kg/day) was administrated by gavage from pregnancy day 10 until 19 (n = 8).[2]
On pregnancy day 19, rats were euthanized by overdose of isoflurane followed by exsanguination. Subsequently, a laparotomy was performed for the exposure/removal of the pregnant uterus, and the abdominal aorta was withdrawn. The abdominal aorta was prepared for vascular reactivity experiments. Placental weight and litter size (total number of pups) were recorded. Placenta and plasma were stored at −80 °C until use for biochemical analysis.[2]

Dissolved in water; 30 mg/kg/day; oral administration

Male Wistar rats receiving irradiation for 5 weeks

Pharmacokinetic Properties[1]
After 4 weeks of twice daily 5, 10 and 20mg doses peak plasma pravastatin concentrations and area under the plasma concentration-time curve values increased dose proportionally in patients with primary hypercholesterolaemia. The major metabolite is about 2.5 to 10% as potent as its parent drug with regard to inhibiting HMG-CoA reductase. Pravastatin has a low (17%) systemic availability after an oral dose and does not appear to accumulate with repeated administration. Tissue distribution studies have demonstrated that pravastatin is selectively distributed to hepatic cells, which is consistent with the drug’s selective inhibition of cholesterol synthesis in the liver. Pravastatin is excreted rapidly, with 71 and 20% of a single oral dose recovered in faeces and urine, respectively, within 96 hours. Biliary excretion appears to be marked since after intravenous administration 34% of the drug is recoverable in faeces. The terminal plasma elimination half-life of pravastatin in healthy volunteers and hypercholesterolaemic patients has ranged from 1.3 to 2.6 hours.

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Metabolism / Metabolites
After initial administration, pravastatin undergoes extensive first-pass extraction in the liver. However, pravastatin's metabolism is not related to the activity of the cytochrome P-450 isoenzymes and its processing is performed in a minor extent in the liver. Therefore, this drug is highly exposed to peripheral tissues. The metabolism of pravastatin is ruled mainly by the presence of glucuronidation reactions with very minimal intervention of CYP3A enzymes. After metabolism, pravastatin does not produce active metabolites. This metabolism is mainly done in the stomach followed by a minor portion of renal and hepatic processing. The major metabolite formed as part of pravastatin metabolism is the 3-alpha-hydroxy isomer. The activity of this metabolite is very clinically negligible.

The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3a-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3a-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).

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Biological Half-Life
The reported elimination half-life of pravastatin is reported to be of 1.8 hours.

Following single dose oral administration of (14)C-pravastatin, the radioactive elimination half life for pravastatin is 1.8 hours in humans.

In a two-way crossover study, eight healthy male subjects each received an intravenous and an oral dose of (14)C-pravastatin sodium. ... The estimated average plasma elimination half-life of pravastatin was 0.8 and 1.8 hr for the intravenous and oral routes, respectively. ...

Toxicity Summary
IDENTIFICATION AND USE: Pravastatin, a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor (i.e., statin), is an antilipemic agent. Pravastatin occurs as an odorless, white to off-white, fine or crystalline powder formulated into a tablet. It is used as an adjunct to lifexstyle modifications for prevention of cardiovascular events and for the management of dyslipidemias. HUMAN EXPOSURE AND TOXICITY: Pravastatin is contraindicated for use in pregnant woman because of the potential for fetal harm. There have also been rare reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. Also, rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. ANIMAL STUDIES: Acute studies were performed in both mice and rats. Signs of toxicity in mice were decreased activity, irregular respiration, ptosis, lacrimation, soft stool, diarrhea, urine-stained abdomen, ataxia, creeping behavior, loss of righting reflex, hypothermia, urinary incontinence, pilo-erection convulsion and/or prostration. Signs of toxicity in rats were soft stool, diarrhea, decreased activity, irregular respiration, waddling gait, and ataxia, loss of righting reflex and/or weight loss. In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg bw, there was an increased incidence of hepatocellular carcinomas in males at the highest dose. Likewise, in a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females; lung adenomas in females were increased. In dogs, pravastatin sodium was toxic at high doses and caused cerebral hemorrhage with clinical evidence of acute CNS toxicity such as ataxia, convulsions. The threshold dose for CNS toxicity is 25 mg/kg. Cerebral hemorrhages have not been observed in any other laboratory species and the CNS toxicity in dogs may represent a species-specific effect. In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and increased cervical rib skeletal anomalies were observed at >/= 100 mg/kg/day. In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning), increased mortality of offspring and developmental delays were observed at >/= 100 mg/kg/day. In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance. No evidence of mutagenicity was observed in vitro, with or without metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/- mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.

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Hepatotoxicity
Pravastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in 3% to 7% of patients; but levels above 3 times the upper limit of normal (ULN) occurred in less than 1.2% of both pravastatin- as well as in placebo-treated subjects. Most of these elevations were self-limited and did not require dose modification. Pravastatin has been only rarely associated with clinically apparent hepatic injury with symptoms or jaundice at a rate estimated to be 1 per 100,000 users or less. In the case reports, latency varied from 2 to 9 months and the pattern of serum enzyme elevations from cholestatic to hepatocellular. Recovery was complete within a few months. Rash, fever and eosinophilia were uncommon as were autoantibodies, but few cases have been reported and the full clinical syndrome not well defined. Pravastatin appears to be less likely to cause clinically apparent liver injury than atorvastatin, simvastatin and rosuvastatin.
Likelihood score: B (likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Levels of pravastatin in milk are low, but no relevant published information exists with its use during breastfeeding. The consensus opinion is that women taking a statin should not breastfeed because of a concern with disruption of infant lipid metabolism. However, others have argued that children homozygous for familial hypercholesterolemia are treated with statins beginning at 1 year of age, that statins have low oral bioavailability, and risks to the breastfed infant are low, especially with pravastatin and rosuvastatin. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Due its polarity, pravastatin binding to plasma proteins is very limited and the bound form represents only about 43-48% of the administered dose. However, the activity of p-glycoprotein in luminal apical cells and OATP1B1 produce significant changes to pravastatin distribution and elimination.

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16759173 man TDLo oral 16 mg/kg/8W-I LIVER: JAUNDICE, CHOLESTATIC; LIVER: LIVER FUNCTION TESTS IMPAIRED; SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE American Journal of Emergency Medicine., 17(1388), 1999
16759173 women TDLo oral 16800 ug/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Lancet., 340(910), 1992
16759173 women TDLo oral 30 mg/kg/21W-I BEHAVIORAL: MUSCLE WEAKNESS; BLOOD: CHANGES IN SERUM COMPOSITION (E.G., TP, BILIRUBIN, CHOLESTEROL); SKIN AND APPENDAGES (SKIN): DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE New England Journal of Medicine., 327(649), 1992
16759173 rat LD50 oral >12 gm/kg Yakkyoku. Pharmacy., 40(2351), 1989
16759173 rat LD50 subcutaneous 3172 mg/kg BEHAVIORAL: ATAXIA; LUNGS, THORAX, OR RESPIRATION: OTHER CHANGES; SKIN AND APPENDAGES (SKIN): HAIR: OTHER Yakuri to Chiryo. Pharmacology and Therapeutics., 15(4949), 1987

[1]. Pravastatin. A review of its pharmacological properties and therapeutic potential in hypercholesterolaemia. Drugs. 1991 Jul;42(1):65-89.

[2]. Pravastatin Prevents Increases in Activity of Metalloproteinase-2 and Oxidative Stress, and Enhances Endothelium-Derived Nitric Oxide-Dependent Vasodilation in Gestational Hypertension. Antioxidants (Basel) . 2023 Apr 16;12(4):939.

Pravastatin sodium can cause developmental toxicity according to state or federal government labeling requirements.
Pravastatin sodium is an organic sodium salt that is the sodium salt of pravastatin. A reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), it is used for lowering cholesterol and preventing cardiovascular disease. It is one of the lower potency statins, but has the advantage of fewer side effects compared with lovastatin and simvastatin. It has a role as an anticholesteremic drug. It is an organic sodium salt and a statin (semi-synthetic). It contains a pravastatin(1-).
Pravastatin Sodium is the sodium salt of pravastatin with cholesterol-lowering and potential antineoplastic activities. Pravastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. This agent lowers plasma cholesterol and lipoprotein levels, and modulates immune responses by suppressing MHC II (major histocompatibility complex II) on interferon gamma-stimulated, antigen-presenting cells such as human vascular endothelial cells. In addition, pravastatin, like other statins, exhibits pro-apoptotic, growth inhibitory, and pro-differentiation activities in a variety of tumor cells; these antineoplastic activities may be due, in part, to inhibition of the isoprenylation of Ras and Rho GTPases and related signaling cascades.
An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES).
See also: Pravastatin (has active moiety); Aspirin; pravastatin sodium (component of).

C23H35O7.NA

446.51

446.228

C, 61.87; H, 7.90; Na, 5.15; O, 25.08

81131-70-6

Pravastatin;81093-37-0;Pravastatin sodium (Standard);81131-70-6;Pravastatin-13C,d3 sodium; 85956-22-5 (lactone);

16759173

Off-white to Pale purple solid powder

634.5ºCat 760 mmHg

171.2-173 °C

213.2ºC

2.44

124.29

3

7

11

31

662

8

CC[C@H](C)C(=O)O[C@H]1C[C@@H](C=C2[C@H]1[C@H]([C@H](C=C2)C)CC[C@H](C[C@H](CC(=O)[O-])O)O)O.[Na+]

VWBQYTRBTXKKOG-IYNICTALSA-M

InChI=1S/C23H36O7.Na/c1-4-13(2)23(29)30-20-11-17(25)9-15-6-5-14(3)19(22(15)20)8-7-16(24)10-18(26)12-21(27)28;/h5-6,9,13-14,16-20,22,24-26H,4,7-8,10-12H2,1-3H3,(H,27,28);/q;+1/p-1/t13-,14-,16+,17+,18+,19-,20-,22-;/m0./s1

sodium;(3R,5R)-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(2S)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydroxyheptanoate

Apotex; CS-514 Sodium, Pravachol; Selektine; Pravaselect; Apo-Pravastatin; Mevalotin; Elisor; Lipostat; Pravastatin Sodium; Aventis; Bristacol; CS 514; CS-514; CS514;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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 (5.60 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 (5.60 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 (5.60 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。

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配方 4 中的溶解度: 100 mg/mL (223.96 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.

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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。