Beta-1 adrenergic receptor

比索洛尔（2 μM，1 小时）可保护心肌细胞 (H9c2) 免受缺血/再灌注 (I/R) 损伤[2]。 Bisoprolol（2 μM，1 小时）可减少 H9c2 细胞中 H/R 诱导的 ROS 产生和细胞凋亡[2]。比索洛尔（2 μM，1 小时）可增加 H9c2 细胞中 AKT 和 GSK3β 的磷酸化[2]。 Bisoprolol（100 μM，24 小时）通过增加 β-arrestin 2、CCR7 和 PI3K 磷酸化来逆转胆固醇负载 DC（树突状细胞）中肾上腺素抑制的迁移[3]。细胞活力测定[2] 细胞系：H9c2 细胞 浓度：0.2、2、20 μM 孵育时间：1 h 结果：H/R（缺氧/复氧）心肌细胞存活率提高至 73.20%、90.38%、81.25 ％ 分别。细胞迁移测定 [3] 细胞系：DC 浓度：100 μM 孵育时间：6、12、24 小时 结果：迁移细胞数量增加 46.00%（6 小时）、64.25%（12 小时）和 55.74%（24 H）。

比索洛尔（口服，5 mg/kg，持续1周）可增加左心室射血分数（LVEF）并降低心率值[2]。比索洛尔（口服灌胃，8 mg/kg，每天，持续四周）对大鼠镉诱导的心肌毒性具有保护作用[4]。比索洛尔（口服灌胃，1 mg/kg，每天，持续 6 周）可逆转容量超负荷大鼠模型中的小电导钙激活钾通道 (SK) 重塑[5]。动物模型：缺血/再灌注（I/R）损伤大鼠[2] 剂量：0.5、5、10 mg/kg 给药方法：口服给药，持续1周，在0.5小时缺血/4小时再灌注之前。结果：梗死面积从 I/R 组的 44% 减少到治疗组的 31%。动物模型：镉诱导大鼠[4] 剂量：2、8 mg/kg 给药方法：口服灌胃，每天一次，持续四个星期。结果：平均动脉压 (MAP) 降低至 8 mg/kg。 8 mg/kg 时血清生物标志物（ALT、AST）和 NF-kB p65 表达以及 TNF-α 水平（心脏组织样本）降低。

细胞系：H9c2细胞
浓度：0.2、2、20 μM
孵育时间：1 h
结果：H/R（缺氧/复氧）心肌细胞存活率提高至73.20%、90.38 %、81.25%。

Ischemia/reperfusion (I/R) injury rats
0.5, 5, 10 mg/kg
Oral administration, for 1 week, prior to 0.5 h ischemia/4 h reperfusion.

Absorption, Distribution and Excretion
Bisoprolol is well absorbed in the gastrointestinal tract. The AUC is 642.87 g.hr/mL and bioavailability of bisoprolol is about 90% due to the minimal first pass effects. Absorption is unaffected by food intake. Peak plasma concentrations of bisoprolol are attained within 2-4 hours and steady-state concentrations are achieved within 5 days of administration. In a pharmacokinetic study, the mean peak concentration of bisoprolol was 52 micrograms/L. Cmax at steady state concentrations of bisoprolol is 64±21 ng/ml administered at 10 mg daily.
Bisoprolol is eliminated equally by both renal and hepatic pathways. About 50% of an oral dose is excreted unchanged in the urine with the remainder of the dose excreted as inactive bisoprolol metabolites. Under 2% of the ingested dose is found to be excreted in the feces.
The volume of distribution of bisoprolol is 3.5 L/kg. The mean volume of distribution was found to be 230 L/kg in heart failure patients, which was similar to the volume of distribution in healthy patients. Bisoprolol is known to cross the placenta.
Total body clearance in healthy patients was determined to be 14.2 L/h. In patients with renal impairment, clearance was reduced to 7.8 L/h. Hepatic dysfunction also reduced the clearance of bisoprolol.
Beagles were treated with bisoprolol, a beta 1-selective adrenoceptor antagonist, for 30 days with the following daily doses: oral: 30 mg/kg; conjunctival: 0.5% solution (approx. 0.04 mg/kg) and 5% solution (approx. 0.4 mg/kg). Drug concentrations were determined in plasma and various eye tissues on days 1, 16, and 30, and on day 59, i.e. on day 29 of the follow-up period. Bisoprolol concentrations in plasma and most eye tissues were considerably higher after oral than after conjunctival treatment. The highest tissue concentrations were observed in the iris (+ciliary body) and retina (+choroid) with tissue/plasma concentration ratios between 100 and 150 after oral and 1000 to 3000 after conjunctival instillation (5% solution). In plasma no accumulation of the drug was observed which is in accordance with its plasma half-life of 4 to 5 hr. In contrast to this, concentrations in the iris and retina increased from day 1 to day 16 and 30 by 3 to 8 times and the half-life of bisoprolol in these tissues was estimated to be between 3 to 5 days.
The pharmacokinetic properties of bisoprolol-(14)C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. Bisoprolol is well absorbed in these species; independent of the route of administration (IV or PO), 70-90% of the (14)C-dose was recovered in urine. Fecal excretion was approximately 20% in rats and less than 10% in dogs and monkeys. Rats excreted approximately 10% of the dose in bile after IV as well as after oral administration. The plasma half-life of the unchanged drug was approximately 1 hr in rats, 3 hr in monkeys, and 5 hr in dogs. The bioavailability was 40-50% in monkeys, approximately 80% in dogs, and 10% in rats. Studies in rats have shown that the drug is rapidly taken up by the tissues. After IV administration, high levels of radioactivity were found in lung, kidneys, liver, adrenals, spleen, pancreas, and salivary glands. After oral administration, the highest concentration occurred in the liver and kidneys. With the exception of plasma and liver, unchanged bisoprolol was the major radioactive constituent in all tissues studied. Both the blood-brain and placental barriers were penetrated, but only to a small degree. No accumulation of radioactivity in tissues was observed after repeated dosing (1 mg/kg/day). The metabolism of bisoprolol was studied in the same three animal species and in humans. The major metabolites are the products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. The amount of bisoprolol excreted unchanged in the urine is 50-60% of the dose in humans, 30-40% in dogs, and approximately 10% in rats and monkeys.
The pharmacokinetics of bisoprolol (I) following an oral dose of 20 mg (14)C-labeled I solution, 10 mg tablet, and intravenous injection of 10 mg I were studied in 23 healthy volunteers (aged 37-53 yr). Mean elimination half-lives of 11 h for the unchanged I and 12 h for total radioactivity were observed. The enteral absorption of I was nearly complete. Fifty percent of the dose was eliminated renally as unchanged I and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral or IV dose yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 l/h and 9.6 l/h, respectively. The volume of distribution was 226 l. Concomitant food intake did not influence the bioavailability of I.
We previously reported that renal function is partly responsible for the interindividual variability of the pharmacokinetics of bisoprolol. The aim of the present study was to examine the variability of bioavailability (F) of bisoprolol in routinely treated Japanese patients and intestinal absorption characteristics of the drug. We first analyzed the plasma concentration data of bisoprolol in 52 Japanese patients using a nonlinear mixed effects model. We also investigated the cellular uptake of bisoprolol using human intestinal epithelial LS180 cells. The oral clearance (CL/F) of bisoprolol in Japanese patients was positively correlated with the apparent volume of distribution (V/F), implying variable F. The uptake of bisoprolol in LS180 cells was temperature-dependent and saturable, and was significantly decreased in the presence of quinidine and diphenhydramine. In addition, the cellular uptake of bisoprolol dissolved in an acidic buffer was markedly less than that dissolved in a neutral buffer. These findings suggest that the rate/extent of the intestinal absorption of bisoprolol is another cause of the interindividual variability of the pharmacokinetics, and that the uptake of bisoprolol in intestinal epithelial cells is highly pH-dependent and also variable.
For more Absorption, Distribution and Excretion (Complete) data for Bisoprolol (9 total), please visit the HSDB record page.

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Metabolism / Metabolites
Approximately 50% of the bisoprolol dose is eliminated by non-renal pathways. Bisoprolol is metabolized through oxidative metabolic pathways with no subsequent conjugation. Bisoprolol metabolites are polar and, therefore, really eliminated. Major metabolites found in plasma and urine are inactive. Bisoprolol is mainly metabolized by CYP3A4 (95%), whereas CYP2D6 plays a minor role. The CYP3A4-mediated metabolism of bisoprolol appears to be non-stereoselective.
... In humans, the known metabolites are labile or have no known pharmacologic activity. ... Bisoprolol fumarate is not metabolized by cytochrome P450 II D6 (debrisoquin hydroxylase).
The plasma concentrations and urinary excretions of bisoprolol enantiomers in four Japanese male healthy volunteers after a single oral administration of 20 mg of racemic bisoprolol were evaluated. The AUC(infinity) and elimination half-life of (S)-(-)-bisoprolol were slightly larger than those of (R)-(+)-bisoprolol in all subjects. The metabolic clearance of (R)-(+)-bisoprolol was significantly (P < 0.05) larger than that of (S)-(-)-bisoprolol (S/R ratio: 0.79+/-0.03), although the difference was small. In contrast, no stereoselective in vitro protein binding of bisoprolol in human plasma was found. An in vitro metabolic study using recombinant human cytochrome P450 (CYP) isoforms indicated that oxidation of both bisoprolol enantiomers was catalyzed by the two isoforms, CYP2D6 and CYP3A4. CYP2D6 metabolized bisoprolol stereoselectively (R > S), whereas the metabolism of bisoprolol by CYP3A4 was not stereoselective. The S/R ratio of the mean clearance due to renal tubular secretion was 0.68, indicating a moderate degree of stereoselective renal tubular secretion. These findings taken together suggest that the small differences in the pharmacokinetics between (S)-(-)- and (R)-(+)-bisoprolol are mainly due to the stereoselectivity in the intrinsic metabolic clearance by CYP2D6 and renal tubular secretion.
The pharmacokinetic properties of bisoprolol-(14)C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. ... The metabolism of bisoprolol was studied in the same three animal species and in humans. The major metabolites are the products of O-dealkylation and subsequent oxidation to the corresponding carboxylic acids. ...

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Biological Half-Life
A pharmacokinetic study in 12 healthy individuals determined the mean plasma half-life of bisoprolol to be 10-12 hours. Another study comprised of healthy patients determined the elimination half-life to be approximately 10 hours. Renal impairment increased the half-life to 18.5 hours.
In patients with cirrhosis of the liver, the elimination of Zebeta (bisoprolol fumarate) is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging from 8.3 to 21.7 hours.
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately threefold compared to healthy subjects.
The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part because of decreased renal function in that population.
The pharmacokinetic properties of bisoprolol-(14)C were studied in Wistar rats, beagle dogs, and Cynomolgus monkeys. ... The plasma half-life of the unchanged drug was approximately 1 hr in rats, 3 hr in monkeys, and 5 hr in dogs.
In dogs, bisoprolol has ... a half life of 4 hours

Hepatotoxicity
Bisoprolol therapy has been associated with a low rate of mild-to-moderate elevations of serum aminotransferase levels which are usually asymptomatic and transient and resolve even with continuation of therapy. There have been no well documented cases of clinically apparent, acute liver injury attributable to bisoprolol. Thus, hepatotoxicity due to bisoprolol must be very rare, if it occurs at all. Most commonly used beta-blockers have been linked to rare instances of clinically apparent liver injury, typically with onset within 2 to 12 weeks, a hepatocellular pattern of liver enzyme elevations, rapid recovery upon withdrawal, and little evidence of hypersensitivity (rash, fever, eosinophilia) or autoantibody formation.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that a maternal dose of 5 mg daily produces low levels in milk and some follow-up date indicate no adverse long-term effects on the breastfed infant. If bisoprolol is required by the mother, it is not a reason to discontinue breastfeeding. Other beta-blockers with more safety data may be preferred.
◉ Effects in Breastfed Infants
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.
A prospective study followed 11 women who were taking bisoprolol in a median dose was 2.5 mg daily (range 1 to 5 mg) during breastfeeding (8 exclusively). The median age of the child at the time of follow-up was 49 (IRQ 25.5to 58.5) months. Adverse effects were reported among 2 infants: 1 with somnolence and 1 with poor weight gain. No abnormal results were found by Denver developmental scale. Median psychomotor development according to PEDsQL score total 97.5, psychosocial health 97.9 and physical health 100, all representing normal development.
◉ Effects on Lactation and Breastmilk
A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol. Relevant published information on the effects of beta-blockade or bisoprolol during normal lactation was not found as of the revision date.

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Protein Binding
Binding to serum proteins is approximately 30%.

[1]. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors. Br J Pharmacol. 2005 Feb;144(3):317-22.

[2]. Bisoprolol, a β 1 antagonist, protects myocardial cells from ischemia-reperfusion injury via PI3K/AKT/GSK3β pathway. Fundam Clin Pharmacol. 2020 Dec;34(6):708-720.

[3]. Bisoprolol reverses epinephrine-mediated inhibition of cell emigration through increases in the expression of β-arrestin 2 and CCR7 and PI3K phosphorylation, in dendritic cells loaded with cholesterol. Thromb Res. 2013 Mar;131(3):230-7.

[4]. Protective Effects of Bisoprolol Against Cadmium-induced Myocardial Toxicity Through Inhibition of Oxidative Stress and NF-κΒ Signalling in Rats. J Vet Res. 2021 Oct 20;65(4):505-511.

[5]. Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model. Mol Cell Biochem. 2013 Dec;384(1-2):95-103.

Bisoprolol is a secondary alcohol and a secondary amine. It has a role as an antihypertensive agent, a beta-adrenergic antagonist, an anti-arrhythmia drug and a sympatholytic agent.
Bisoprolol is a cardioselective β1-adrenergic blocking agent used to treat high blood pressure. It is considered a potent drug with a long-half life that can be used once daily to reduce the need for multiple doses of antihypertensive drugs. Bisoprolol is generally well tolerated, likely due to its β1-adrenergic receptor selectivity and is a useful alternative to non-selective β-blocker drugs in the treatment of hypertension such as [Carvedilol] and [Labetalol]. It may be used alone or in combination with other drugs to manage hypertension and can be useful in patients with chronic obstructive pulmonary disease (COPD) due to its receptor selectivity.
Bisoprolol is a beta-Adrenergic Blocker. The mechanism of action of bisoprolol is as an Adrenergic beta-Antagonist.
Bisoprolol is a cardioselective beta-blocker used in the treatment of hypertension. Bisoprolol has not been linked to instances of clinically apparent drug induced liver injury.
Bisoprolol Fumarate is the fumarate salt of a synthetic phenoxy-2-propanol-derived cardioselective beta-1 adrenergic receptor antagonist with antihypertensive and potential cardioprotective activities. Devoid of intrinsic sympathomimetic activity, bisoprolol selectively and competitively binds to and blocks beta-1 adrenergic receptors in the heart, decreasing cardiac contractility and rate, reducing cardiac output, and lowering blood pressure. In addition, this agent may exhibit antihypertensive activity through the inhibition of renin secretion by juxtaglomerular epithelioid (JGE) cells in the kidney, thus inhibiting activation of the renin-angiotensin system (RAS). Bisoprolol has been shown to be cardioprotective in animal models.
Bisoprolol is a selective beta-1 adrenergic receptor antagonist with antihypertensive activity and devoid of intrinsic sympathomimetic activity. Bisoprolol selectively and competitively binds to and blocks beta-1 adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. In addition, bisoprolol prevent the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels.
A cardioselective beta-1 adrenergic blocker. It is effective in the management of HYPERTENSION and ANGINA PECTORIS.
See also: Bisoprolol Fumarate (has salt form).

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Drug Indication
Bisoprolol is indicated for the treatment of mild to moderate hypertension. It may be used off-label to treat heart failure, atrial fibrillation, and angina pectoris.

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Mechanism of Action
Though the mechanism of action of bisoprolol has not been fully elucidated in hypertension, it is thought that therapeutic effects are achieved through the antagonism of β-1adrenoceptors to result in lower cardiac output. Bisoprolol is a competitive, cardioselective β1-adrenergic antagonist. When β1-receptors (located mainly in the heart) are activated by adrenergic neurotransmitters such as epinephrine, both the blood pressure and heart rate increase, leading to greater cardiovascular work, increasing the demand for oxygen. Bisoprolol reduces cardiac workload by decreasing contractility and the need for oxygen through competitive inhibition of β1-adrenergic receptors. Bisoprolol is also thought to reduce the output of renin in the kidneys, which normally increases blood pressure. Additionally, some central nervous system effects of bisoprolol may include diminishing sympathetic nervous system output from the brain, decreasing blood pressure and heart rate.

C18H31NO4

325.44

325.225

C, 66.43; H, 9.60; N, 4.30; O, 19.66

66722-44-9

Bisoprolol-d5; 1189881-87-5; Bisoprolol hemifumarate; 104344-23-2; Bisoprolol fumarate; 105878-43-1

2405

Colorless to light yellow liquid

1.0±0.1 g/cm3

445.0±45.0 °C at 760 mmHg

100-103
100 °C

222.9±28.7 °C

0.0±1.1 mmHg at 25°C

1.500

2.14

59.95

2

5

12

23

278

0

CC(OCCOCC1=CC=C(OCC(CNC(C)C)O)C=C1)C

VHYCDWMUTMEGQY-UHFFFAOYSA-N

InChI=1S/C18H31NO4/c1-14(2)19-11-17(20)13-23-18-7-5-16(6-8-18)12-21-9-10-22-15(3)4/h5-8,14-15,17,19-20H,9-13H2,1-4H3

1-(propan-2-ylamino)-3-[4-(2-propan-2-yloxyethoxymethyl)phenoxy]propan-2-ol

CL297,939; CL-297,939; Bisoprolol; CL 297,939

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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;
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