ACE/angiotensin-converting enzyme

已经证明，在高血压患者中，卡托普利 (SQ 14225) 的发病率和有效性与利尿剂和 β 受体阻滞剂相似。已证明卡托普利可减缓糖尿病肾病的进展，但依那普利和赖诺普利可阻止白蛋白尿正常的糖尿病患者的疾病进展[4]。该溶液含有等摩尔比例的顺式和反式卡托普利，酶专门选择化合物的反式形式。该酶及其底物结合碱基表现出结构和立体电子互补性[5]。

卡托普利是一种ACE抑制剂，可拮抗RAAS的作用。RAAS是一种稳态机制，用于调节血流动力学、水和电解质平衡。在交感神经刺激期间或当肾血压或血流量降低时，肾素从肾脏肾小球旁器的颗粒细胞中释放。在血流中，肾素将循环血管紧张素原切割为ATI，随后通过ACE将其切割为ATII。ATII通过多种机制提高血压。首先，它刺激肾上腺皮质分泌醛固酮。醛固酮进入肾单位的远曲小管（DCT）和集合管，在那里它通过增加细胞膜上钠通道和钠钾ATP酶的数量来增加钠和水的重吸收。其次，ATII刺激垂体后叶分泌加压素（也称为抗利尿激素或ADH）。ADH通过在DCT和集合管细胞的顶端表面插入水通道蛋白2通道，刺激肾脏进一步吸收水分。第三，ATII通过直接动脉血管收缩来提高血压。刺激血管平滑肌细胞上的1型ATII受体会导致一连串的事件，导致肌细胞收缩和血管收缩。除了这些主要作用外，ATII还通过刺激下丘脑神经元来诱导口渴反应。ACE抑制剂抑制ATI向ATII的快速转化，并拮抗RAAS诱导的血压升高。ACE（也称为激肽酶II）也参与血管舒张剂缓激肽的酶促失活。抑制缓激肽的失活会增加缓激肽水平，并可能通过引起血管舒张增加和血压下降来维持其作用。

ACE抑制测定[1]
使用Chang等人描述的以HHL为底物的分光光度法测量不同浓度的EA和CP对ACE活性的抑制作用及其IC50值。简言之，含有0.3M NaCl（pH 8.3）的20mM硼酸钠缓冲液用于制备EA、CP、ACE和底物HHL溶液。ACE催化反应在37°C下在以下组成的试管中进行30分钟：100μL EA或CP、100μL ACE溶液（40mU/mL）和100μL HHL（15mM）溶液（A1）；100μL EA或CP溶液和200μL硼酸盐缓冲液（A2）；100μL硼酸盐缓冲液、100μL ACE溶液和100μL HHL溶液（A3）；和300μL硼酸盐缓冲液（A4）。通过加入3mL OPA溶液的碱性溶液（pH 12.0）来停止酶促反应。在25°C下孵育20分钟后，使用Beckman DU-640在390nm处测量每个反应的吸光度。使用以下方程计算EA或CP对ACE的抑制作用：抑制作用（%）=[1–（A1–A2）/（A3–A4）]×100。ACE活性的IC50值通过方程IC50=（50–b）/m计算，该方程源自ACE活性的线性回归图，其中b是截距，m是方程的斜率。

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ACE抑制动力学参数的测定[1]
根据Michaelis–Menten动力学模型确定Vmax和Km值的动力学参数。通过上述方法测定ACE（40mU/mL）在有EA（0.091μM）或CP（0.00625μM）和没有EA或CP的情况下由HHL形成l-组氨酸-l-亮氨酸的反应速率，得到饱和曲线，然后绘制与HHL浓度（0.94、1.85、3.75、7.50、15mM）的关系图。Lineweaver–Burk图是使用饱和曲线得出的，以确定抑制的类型。使用MS Excel计算动力学参数（Km和Vmax）。

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研究了含巯基的血管紧张素转换酶ACE竞争性抑制剂卡托普利对碳酸酐酶CA酯酶活性的抑制作用。选择这种小分子，以及依那普利，是为了代表硫醇和羧酸盐，作为金属蛋白抑制剂的两个众所周知的金属结合官能团。由于卡托普利也被观察到通过与催化金属离子结合来抑制其他金属酶，如酪氨酸酶和金属β-内酰胺酶，并且将CA视为一种含锌的金属酶，在本研究中，我们开始确定卡托普利/依那普利是否抑制纯化的人CA II的CA酯酶活性？然后，我们揭示了抑制剂的效力（IC50、Ki和Kdiss值）以及抑制模式。我们的结果还表明，依那普利是比卡托普利更有效的CA抑制剂。由于依那普利不代表巯基部分，因此羧酸基团可能在抑制CA酯酶活性中起决定作用，这一结论通过分子对接研究得到了证实。此外，由于卡托普利/依那普利对CA的抑制能力远低于经典磺酰胺类药物，因此当前研究的结果可以解释为什么这些药物在体内达到的浓度下没有表现出有效的CA抑制作用，也可以阐明产生新一类抑制剂的方法，这些抑制剂将区别性地抑制各种CA异构体[2]。

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%[5].

Absorption, Distribution and Excretion
60-75% in fasting individuals; food decreases absorption by 25-40% (some evidence indicates that this is not clinically significant)
The drug /captopril/ is metabolized and renally excreted. More than 95% of a dose is excreted renally, both as unchanged (45-50%) drug and as metabolites.
In dogs, approximately 75% of an oral dose is absorbed but food in the GI tract reduces bioavailability by 30-40%. It is distributed to most tissues (not the CNS) and is 40% bound to plasma proteins in dogs.
Approximately 60-75% of an oral dose of captopril is rapidly absorbed from the GI tract in fasting healthy individuals or hypertensive patients. Food may decrease absorption of captopril by up to 25-40%, although there is some evidence that this effect is not clinically important. Following oral administration of a single 100-mg dose of captopril in fasting healthy individuals in one study, average peak blood drug concentrations of 800 ng/mL were attained in 1 hour.
/MILK/ Concentrations of captopril in human milk are approximately one percent of those in maternal blood.
For more Absorption, Distribution and Excretion (Complete) data for Captopril (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic. Major metabolites are captopril-cysteine disulfide and the disulfide dimer of captopril. Metabolites may undergo reversible interconversion.
About half the absorbed dose of captopril is rapidly metabolized, mainly to captopril-cysteine disulfide and the disulfide dimer of captopril. In vitro studies suggest that captopril and its metabolites may undergo reversible interconversions. It has been suggested that the drug may be more extensively metabolized in patients with renal impairment than in patients with normal renal function.

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Biological Half-Life
2 hours
A 43 year old patient with mild heart failure attempted suicide by ingesting between 5000 and 7500 mg of captopril. Blood pressure oscillated around 100-120/50-75 mm Hg and pulse rate showed no tendency to accelerate (75-100/min). ... The calculated half-life of captopril was 4.4 hr. ...
The half life of captopril is about 2.8 hours in dogs ... .
The elimination half-life of unchanged captopril appears to be less than 2 hours in patients with normal renal function. The elimination half-life of captopril and its metabolites is correlated with creatinine clearance and increases to about 20-40 hours in patients with creatinine clearances less than 20 mL/minute and as long as 6.5 days in anuric patients.

Toxicity Summary
IDENTIFICATION AND USE: Captopril is angiotensin-converting enzyme (ACE) inhibitor and antihypertensive agent. HUMAN STUDIES: Captopril prevents the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor) by competing with the physiologic substrate (angiotensin I) for the active site of ACE. The affinity of the drug for ACE is approximately 30,000 times greater than that of angiotensin I. Inhibition of ACE results in decreased plasma angiotensin II concentrations and, consequently, blood pressure may be reduced in part through decreased vasoconstriction. Captopril-induced bone marrow suppression is rare, except in certain high-risk patient populations. Severe exfoliative rashes have also been associated with captopril. A 57 year old male with mild impairment of renal function secondary to diabetic glomerulosclerosis developed acute renal failure associated with a generalized desquamative skin rash and peripheral eosinophilia shortly after initiation of antihypertensive therapy with captopril. Cholestatic jaundice is a rare complication associated with the use captopril. The severity of the disease may range from cholestasis on liver histology to overt fulminant hepatic failure. A case of a 75 year old male who committed suicide by taking an overdose of captopril was reported. He took approximately ninety 12.5 mg captopril tablets. Captopril administration over 3 months or more generates red blood cells zinc depletion. Hypogeusia (a reduced ability to taste things) is a reported side effect of captopril. Linkage of hypogeusia to zinc deficiency has been suggested. The fetal toxicity of captopril in the 2nd and 3rd trimesters is similar to other ACE inhibitors. The use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, prematurity, and patent ductus arteriosus. Still birth or neonatal death may occur. Anuria-associated oligohydramnios may product fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Sever anuria and hypotension, which is resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure. Newborn renal function and blood pressure should be closely monitored. Mutagenicity studies with captopril in fixed combination with hydrochlorothiazide have not been conducted, but the effects of the individual components in a 2:1 ratio have been studied. Captopril/hydrochlorothiazide did not exhibit mutagenic or clastogenic potential in a sister chromatid exchange test in human lymphocytes. In a cytogenetics assay in human lymphocytes exposed to captopril/hydrochlorothiazide concentrations of 5, 25, and 50 ug/mL (total concentration of both drugs) with metabolic activation, chromosomal abnormalities were not observed consistently. When such aberrations were observed, no concentration response was noted. ANIMAL STUDIES: No evidence of carcinogenesis was observed in rats or mice receiving captopril dosages of 50-1350 mg/kg daily for 2 years. Reproduction studies in hamsters and rats using large doses of captopril have not revealed evidence of teratogenic effects. However, the drug was embryocidal and was associated with a low incidence of craniofacial malformations in rabbits, probably as a result of the marked decrease in blood pressure caused by the drug in this species. Reduction in neonatal survival occurred in the offspring of rats receiving captopril continuously during gestation and lactation, and an increased incidence of stillbirths has reportedly occurred in ewes. Mutagenicity studies with captopril in fixed combination with hydrochlorothiazide have not been conducted, but the effects of the individual components in a 2:1 ratio have been studied. Captopril/hydrochlorothiazide did not exhibit mutagenic or clastogenic potential in vitro with or without metabolic activation in a bacterial reverse mutation (Ames) assays using Salmonella, a forward mutation assay in Saccharomyces pombe, and a gene conversion assay using Saccharomyces cerevisiae. Captopril and hydrochlorothiazide in a 2:1 ratio were not genotoxic in the in vivo mouse micronucleus test at an oral dose of 2,500 mg/kg (total concentration of both drugs). ECOTOXICITY STUDIES: Captopril induces oxidative stress in C. carpio.

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Hepatotoxicity
Captopril, like other ACE inhibitors, has been associated with a low rate of serum aminotransferase elevations (
Likelihood score: B (likely but rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the low levels of captopril in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.
◉ Effects in Breastfed Infants
In one report of 12 mothers, several continued to breastfeed their infants while taking captopril 100 mg three times daily. No adverse effects were seen in the infants.[1]
A woman was diagnosed with Cushing's disease during pregnancy. Postpartum she took metyrapone 250 mg 3 times daily, bisoprolol 10 mg twice daily, and captopril 12.5 mg twice daily. She breastfed her preterm infant about 50% milk and 50% formula. At 5 weeks postpartum, the infant's pediatric team found his growth and development to be appropriate.[3]
◉ Effects on Lactation and Breastmilk
In a series of controlled studies reported in one paper, captopril had no effect on the circadian rhythm of prolactin, the response to prolactin-stimulating drugs or serum prolactin in patients with prolactin-secreting tumors.[4]
In a study of young hypertensive males, captopril 25 mg orally markedly decreased serum prolactin at 90 minutes after the dose compared to placebo.[5] The maternal prolactin level in a mother with established lactation may not affect her ability to breastfeed.
In one report, 1 woman out of 12 subjects was unable to produce enough milk for the study while taking captopril 100 mg 3 times daily even though she had been successfully breastfeeding for 6 months.[1] It is not known if this decrease was an effect of captopril.

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Protein Binding
25-30% bound to plasma proteins, primarily albumin

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Interactions
The case of a 70 yr old hypertensive man who presented with a 2 month history of 3 nodular angiomatous lesions on the left arm following treatment with 75 mg/day of oral captopril (Lopril) and 200 mg/day of oral acebutolol hydrochloride (Sectral) for 6 yr is reported. The patient had no history of drug product transfusion, iv drugs, or opportunistic infections. Clinical and histopathological findings were typical of Kaposi's sarcoma. Captopril was stopped, and one month later, the Kaposi's sarcoma lesions had begun to disappear; after 3 months, no lesions were seen. Biopsy showed residual features of Kaposi's sarcoma. However, it is not known whether captopril alone or an interaction with acebutolol hydrochloride resulted in Kaposi's sarcoma.
Concomitant oral administration of captopril and antacids may decrease the rate and extent of GI absorption of captopril. Oral administration of a single, 50-mg dose of captopril 15 minutes after an oral dose of an antacid containing magnesium carbonate and aluminum and magnesium hydroxides resulted in a 40-45% decrease in captopril bioavailability, and a delay and decrease in peak serum concentrations of the drug. However, there is some evidence that this potential interaction may not be clinically important, but additional study is necessary.
Neuropathy reportedly developed in 2 patients receiving captopril and cimetidine. However, further documentation of this potential interaction is necessary.
Initiation of captopril therapy has been associated with unexplained hypoglycemia in several diabetic patients whose diabetes had been controlled with insulin or oral antidiabetic agents. Testing in these patients indicated that captopril may increase insulin sensitivity; the mechanism of this effect is not known. The risk of precipitating hypoglycemia should be considered when captopril therapy is initiated in diabetic patients.
For more Interactions (Complete) data for Captopril (22 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 4245 mg/kg
LD50 Mouse oral 2500 mg/kg
LD50 Mouse iv 663 mg/kg
LD50 Rat iv 554 mg/kg
For more Non-Human Toxicity Values (Complete) data for Captopril (6 total), please visit the HSDB record page.

[1]. Eritadenine from Edible Mushrooms Inhibits Activity of Angiotensin Converting Enzyme in Vitro. J Agric Food Chem. 2016;64(11):2263-2268.

[2]. Captopril/enalapril inhibit promiscuous esterase activity of carbonic anhydrase at micromolar concentrations: An in vitro study. Chem Biol Interact. 2017;265:24-35.

[3]. Simplified captopril analogues as NDM-1 inhibitors. Bioorg Med Chem Lett. 2014;24(1):386-389.

[4]. The molecular basis for the selection of captopril cis and trans conformations by angiotensin I converting enzyme. Bioorg Med Chem Lett, 2006. 16(19): p. 5084-7.

[5]. Song, J.C. and C.M. White, Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet, 2002. 41(3): p. 207-24.

Therapeutic Uses
Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Captopril is included in the database.
Captopril tablets are indicated for the treatment of hypertension. ... Captopril tablets are effective alone and in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of captopril and thiazides are approximately additive. /Included in US product label/
Captopril tablets are indicated in the treatment of congestive heart failure usually in combination with diuretics and digitalis. The beneficial effect of captopril in heart failure does not require the presence of digitalis, however, most controlled clinical trial experience with captopril has been in patients receiving digitalis, as well as diuretic treatment. /Included in US product label/
For more Therapeutic Uses (Complete) data for Captopril (11 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue captopril tablets as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Captopril is generally well tolerated in most patients; however, serious adverse effects (e.g., neutropenia, agranulocytosis, proteinuria, aplastic anemia) have been reported rarely, mainly in patients with renal impairment (especially those with collagen vascular disease). Captopril- induced adverse effects are often alleviated by dosage reduction, occasionally disappear despite continued treatment and without dosage reduction, and are usually reversible following discontinuance of the drug. The most common adverse effects of captopril are rash and loss of taste perception. Adverse effects requiring discontinuance of captopril therapy occur in about 4-12% of patients.
Captopril is contraindicated in patients with known hypersensitivity to the drug or to another angiotension-converting enzyme inhibitor (eg, those who experienced angioedema during therapy with another angiotension-converting enzyme inhibitor).
Patients receiving captopril should be warned not to interrupt or discontinue therapy unless instructed by their physician. Patients with congestive heart failure receiving captopril should be cautioned against rapid increases in physical activity.
For more Drug Warnings (Complete) data for Captopril (32 total), please visit the HSDB record page.

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Pharmacodynamics
Captopril, an ACE inhibitor, antagonizes the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain its effects by causing increased vasodilation and decreased blood pressure.

C9H15NO3S

217.29

217.077

C, 49.75; H, 6.96; N, 6.45; O, 22.09; S, 14.76

62571-86-2

Captopril hydrochloride;198342-23-3;Captopril-d3;1356383-38-4

44093

White to off-white, crystalline powder
Crystals from ethyl acetate/hexane

1.3±0.1 g/cm3

427.0±40.0 °C at 760 mmHg

104-108 °C(lit.)

212.1±27.3 °C

0.0±2.2 mmHg at 25°C

1.551

0.27

96.41

2

4

3

14

244

2

S([H])C([H])([H])[C@@]([H])(C([H])([H])[H])C(N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(=O)O[H])=O

FAKRSMQSSFJEIM-BQBZGAKWSA-N

InChI=1S/C9H15NO3S/c1-6(5-14)8(11)10-4-2-3-7(10)9(12)13/h6-7,14H,2-5H2,1H3,(H,12,13)/t6-,7-/m0/s1

(2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic 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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (11.51 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 (11.51 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 (11.51 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: 32.5 mg/mL (149.57 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。