lipid peroxidation ( IC50 = 5 μM ); Autophagy; β/α-1 adrenergic receptor

体外活性：卡维地洛在大鼠脑匀浆中快速抑制 Fe(++) 引发的脂质过氧化（以硫代巴比妥酸反应物质 (TBARS) 测量），IC50 为 8.1 mM。 Carvedilol 可防止大鼠脑匀浆中 Fe(++) 诱导的 α-生育酚消耗，IC50 为 17.6 mM。卡维地洛剂量依赖性地降低 DMPO-OH 信号的强度，IC50 为 25 mM。卡维地洛对刺激 G(s) 依赖性腺苷酸环化酶具有相反的功效，但会刺激表达 β2 肾上腺素受体 (beta2AR) 的 HEK-293 细胞中先前记录的 G 蛋白偶联受体激酶位点上受体胞质尾部的磷酸化。 Carvedilol (0.1-10 mM) 对人培养的肺动脉血管平滑肌细胞中由血小板衍生生长因子、表皮生长因子、凝血酶和血清刺激的有丝分裂产生浓度依赖性抑制，IC50 值范围为 0.3 mM 至2.0毫米。卡维地洛还对血小板衍生生长因子诱导的血管平滑肌细胞迁移产生浓度依赖性抑制，IC50 值为 3 mM。卡维地洛降低心肌细胞的细胞空泡化程度，并防止阿霉素对心脏和肝脏线粒体呼吸的抑制作用。卡维地洛还可以防止阿霉素引起的线粒体Ca(2+)负载能力下降和心脏线粒体呼吸复合物抑制。细胞测定：卡维地洛有效抑制大鼠脑匀浆中 Fe2+ 引发的脂质过氧化，IC50 为 8.1 μM。在大鼠脑匀浆中，卡维地洛可防止 Fe2+ 诱导的 α-生育酚消耗，IC50 为 17.6 μM。卡维地洛剂量依赖性地降低 DMPO-OH 信号的强度，IC50 为 25 μM。卡维地洛可防止血管损伤后血管平滑肌细胞迁移、增殖和新内膜形成。在人培养的肺动脉血管平滑肌细胞中，卡维地洛（0.1-10 μM）浓度依赖性地抑制血小板衍生生长因子、表皮生长因子、凝血酶和血清刺激的有丝分裂，IC50值范围为0.3至2.0 μM。卡维地洛浓度依赖性地抑制血小板衍生生长因子诱导的血管平滑肌细胞迁移，IC50 值为 3 μM。

在大鼠脑匀浆中，卡维地洛显着降低 Fe2+ 诱导的脂质过氧化，IC50 为 8.1 μM。卡维地洛的 IC50 为 17.6 μM，可防止大鼠脑匀浆中 Fe2+ 诱导的 α-生育酚消耗。卡维洛尔的 IC50 为 25 μM，以剂量依赖性方式降低 DMPO-OH 信号强度。卡维地洛抑制血管损伤后血管平滑肌细胞的迁移、增殖和新生内膜组织的形成。在人培养的肺动脉血管平滑肌细胞中，由血小板源性生长因子、表皮生长因子、凝血酶和血清刺激的有丝分裂被卡维地洛（0.1-10μM）抑制，IC50值范围为0.3-2.0μM。卡维地洛可抑制血小板衍生生长因子诱导的血管平滑肌细胞迁移，IC50 值为 3 μM，呈浓度依赖性。

Absorption, Distribution and Excretion
Carvedilol has a bioavailability of 25-35%. Carvedilol has a Tmax of 1 to 2 hours. Taking carvedilol with a meal increases Tmax without increasing AUC. Carvedilol doses of 50mg lead to a Cmax of 122-262µg/L and an AUC of 717-1600µg/L\*h. Carvedilol doses of 25mg lead to a Cmax of 24-151µg/L and an AUC of 272-947µg/L\*h. Carvedilol doses of 12.5mg lead to a Cmax of 58-69µg/L and an AUC of 208-225µg/L\*h.
16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces.
Carvedilol has a volume of distribution of 1.5-2L/kg or 115L.
The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min.
Carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25 percent to 35 percent due to a significant degree of first-pass metabolism.
Food decreases the rate of the drug's absorption (ie, increases time to peak plasma concentration), but not the extent (ie, no effect on bioavailability) of absorption. Administration with food may decrease the risk of orthostatic hypotension.
Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7 percent of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2 percent of the dose was excreted unchanged in the urine. ... The metabolites of carvedilol are excreted primarily via the bile into the feces.
Carvedilol is more than 98 percent bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range.
For more Absorption, Distribution and Excretion (Complete) data for CARVEDILOL (13 total), please visit the HSDB record page.

---

Metabolism / Metabolites
Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide.
Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation.
Carvedilol is extensively metabolized; phenol ring demethylation and hydroxylation produce 3 metabolites with beta-adrenergic blocking activity and (weak) vasodilating activity. Plasma concentrations of active metabolites are about 10% those of carvedilol. The 4'-hydroxyphenyl metabolite is 13 times more potent than carvedilol in beta-adrenergic blocking activity.
Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects.
For more Metabolism/Metabolites (Complete) data for CARVEDILOL (7 total), please visit the HSDB record page.
Carvedilol has known human metabolites that include (2S,3S,4S,5R)-6-[1-(9H-Carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid.

---

Biological Half-Life
The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported.
The half-life of carvedilol is 7-10 hours; 5-9 hours for R(+)-carvedilol, and 7-11 hours for S(-)-carvedilol.
The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12.5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule Cmax was 66 micrograms.l-1, tmax 1.2 h, t1/2 6.4 h. The t1/2 after i.v. administration was 2.4 h, CL 589 ml/min and VZ 132 l. The absolute bioavailability was 24% (50 mg capsule). The kinetics after the 25 and 50 mg capsules were consistent with dose linearity.

Hepatotoxicity
Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on carvedilol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, carvedilol has been linked to only a single case of clinically apparent liver injury, with injury arising 6 months after starting therapy and a mixed pattern of enzyme elevations without jaundice or signs of hypersensitivity or autoimmunity, and rapid recovery on stopping. Thus, clinically apparent liver injury from carvediol is exceeding rare.
Likelihood score: D (Possible rare cause of clinically apparent liver injury).

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Based on its physicochemical properties, carvedilol appears to present a low-risk to the breastfed infant. Because there is no published experience with carvedilol during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
A study of mothers taking beta-blockers during nursing found a numerically, but not statistically significant increased number of adverse reactions in those taking any beta-blocker. Although the ages of infants were matched to control infants, the ages of the affected infants were not stated. None of the mothers were taking carvedilol.
◉ Effects on Lactation and Breastmilk
Relevant published information on the effects of beta-blockade or carvedilol during normal lactation was not found as of the revision date. A study in 6 patients with hyperprolactinemia and galactorrhea found no changes in serum prolactin levels following beta-adrenergic blockade with propranolol.

---

Protein Binding
Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin.

---

Interactions
Possible conduction disturbance, rarely with hemodynamic compromise. Blood pressure and ECG should be monitored during concomitant use /of carvedilol/ with diltiazem or verapamil.
/Concurrent administration of/ myocardial depressant general anesthetics (ether, cyclopropane, trichloroethylene) /has the/ potential to increased risk of hypotension and heart failure.
/Concurrent administration of/ antidiabetic agents (oral and parenteral [insulin]) /with carvedilol may/ increased /their/ hypoglycemic effect. Blood glucose concentrations should be monitored regularly.
/Concurrent administration of/ catecholamine-depleting agents (eg, reserpine, MAO inhibitors) /may have/ potentially additive effects (eg, hypotension, bradycardia). Patients should be monitored closely for symptoms (eg, vertigo, syncope, postural hypotension).
For more Interactions (Complete) data for CARVEDILOL (22 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Mouse (male and female) oral >8,000 mg/kg
LD50 Rat (male and female) oral >8,000 mg/kg

[1]. J Pharmacol Exp Ther . 1992 Oct;263(1):92-8.

[2]. Proc Natl Acad Sci U S A . 2007 Oct 16;104(42):16657-62.

[3]. Proc Natl Acad Sci U S A . 1993 Jul 1;90(13):6189-93.

[4]. Toxicol Appl Pharmacol . 2002 Dec 15;185(3):218-27.

Therapeutic Uses
Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Vasodilator Agents
Carvedilol is indicated for the treatment of mild-to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and digitalis, to increase survival and, also, to reduce the risk of hospitalization. /Included in US product label/
Carvedilol is indicated to reduce cardiovascular mortality in clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of greater than 40 percent (with or without symptomatic heart failure). /Included in US product label/
Carvedilol is indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. /Included in US product label/
For more Therapeutic Uses (Complete) data for CARVEDILOL (10 total), please visit the HSDB record page.

---

Drug Warnings
Carvedilol is contraindicated in the following conditions: Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have been reported following single doses of carvedilol; second- or third-degree AV block; sick sinus syndrome; severe bradycardia (unless a permanent pacemaker is in place); Patients with cardiogenic shock or who have decompensated heart failure requiring the use of intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy before initiating carvedilol; patients with severe hepatic impairment; patients with a history of a serious hypersensitivity reaction (eg, Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to any component of this medication or other medications containing carvedilol.
Patients with coronary artery disease, who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in angina patients following the abrupt discontinuation of therapy with beta-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other beta-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. Carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of patients with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in patients treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients' underlying disease than to treatment with carvedilol.
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure greater than 100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.
For more Drug Warnings (Complete) data for CARVEDILOL (24 total), please visit the HSDB record page.

---

Pharmacodynamics
Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease.

C24H26N2O4

406.47

406.189

C, 70.92; H, 6.45; N, 6.89; O, 15.74

72956-09-3

(S)-Carvedilol; 95094-00-1; (R)-Carvedilol; 95093-99-5; Carvedilol-d4; 1133705-56-2; Carvedilol metabolite 4-Hydroxyphenyl Carvedilol; 142227-49-4; Carvedilol phosphate hemihydrate; 610309-89-2; Carvedilol-d3; 1020719-25-8; Carvedilol-d5; 929106-58-1

2585

White to off-white solid powder

1.3±0.1 g/cm3

655.2±55.0 °C at 760 mmHg

113-117ºC

350.1±31.5 °C

0.0±2.1 mmHg at 25°C

1.657

4.11

75.74

3

5

10

30

508

0

OC(CNCCOC1=CC=CC=C1OC)COC2=CC=CC(N3)=C2C4=C3C=CC=C4

OGHNVEJMJSYVRP-UHFFFAOYSA-N

InChI=1S/C24H26N2O4/c1-28-21-10-4-5-11-22(21)29-14-13-25-15-17(27)16-30-23-12-6-9-20-24(23)18-7-2-3-8-19(18)26-20/h2-12,17,25-27H,13-16H2,1H3

1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol

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 (6.15 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 (6.15 mM) 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), 悬浊液; 超声助溶。
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。

---

View More

配方 3 中的溶解度: ≥ 2.5 mg/mL (6.15 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。