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

In rat brain homogenate, carvedilol significantly reduced Fe2+-induced lipid peroxidation with an IC50 of 8.1 μM. Carvedilol had an IC50 of 17.6 μM and prevented Fe2+-induced α-tocopherol depletion in rat brain homogenate. With an IC50 of 25 μM, carvingilol reduced the DMPO-OH signal's intensity in a dose-dependent manner. Carvedilol inhibited the migration, proliferation, and formation of neointimal tissue in vascular smooth muscle cells after vascular injury. The mitogenesis that was stimulated by platelet-derived growth factor, epidermal growth factor, thrombin, and serum was inhibited in human cultured pulmonary artery vascular smooth muscle cells by carvedilol (0.1–10 μM), with IC50 values ranging from 0.3 to 2.0 μM. Platelet-derived growth factor-induced vascular smooth muscle cell migration was inhibited by carvedilol with an IC50 value of 3 μM, concentration-dependently.

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.

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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.

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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).

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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.

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

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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.

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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.

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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.

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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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.5 mg/mL (6.15 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)