(-)-Epigallocatechin gallate (EGCG) has a Ki value of 19.4 μM and competitively inhibits OATP1A2-mediated nadolol absorption in human embryonic kidney 293 cells. The Km of OATP1A2 for nadolol is 84 μM [2].

Administering nadolol (20 mg/kg) to male OF1 mice carrying B16F10 tumor cells blocked the neuroendocrine response, which led to fewer and smaller lung metastases in subjects subjected to acute social stress.[3]

Absorption, Distribution and Excretion
Nadolol has an oral absorption rate of approximately 30%. In healthy subjects, after oral administration of 60 mg nadolol, the time to peak concentration (Tmax) was 2.7 hours, and the peak plasma concentration (Cmax) was 69 ± 15 ng/mL; after oral administration of 120 mg nadolol, the peak plasma concentration (Cmax) was 132 ± 27 ng/mL. The AUC after oral administration of 60 mg nadolol was 1021 ng·h/mL, and the AUC after oral administration of 120 mg nadolol was 1913 ± 382 ng·h/mL. Nadolol is not metabolized by the liver and is primarily excreted in the urine. In healthy subjects, after intravenous administration, 60% of the dose is excreted in the urine and 15% in the feces after 72 hours. The remaining dose is expected to be subsequently excreted in the feces. The volume of distribution of nadolol in healthy subjects is 147–157 liters. In healthy subjects, the total clearance of naldolol was 219-250 mL/min, and the renal clearance was 131-150 mL/min. After oral administration of naldolol, absorption varies among individuals, averaging approximately 30-40% of the dose. The presence of food in the gastrointestinal tract does not affect the rate or extent of absorption. After oral administration of 2 mg naldolol (capsules), peak plasma concentrations typically occur within 2-4 hours. A study in hypertensive adult patients showed that after daily administration of 80 mg, 160 mg, or 320 mg naldolol, the mean steady-state plasma concentrations were 25.5-35.5 ng/ml, 51.7-74.1 ng/ml, and 154-191.4 ng/ml, respectively. With daily administration of 40-320 mg naldolol, its antihypertensive and antianginal effects last for at least 24 hours. In a study of patients with normal renal function, approximately 24.6% and 76.9% of the radioactive material were recovered from urine and feces, respectively, within 4 days after oral administration of 2 mg of radiolabeled naldolol (capsules). Nadolol is widely distributed throughout the body. In dogs, trace amounts of naldolol were detected in brain tissue; in rats, the drug crosses the placenta. The drug is distributed in bile. Nadolol is distributed in milk. Approximately 30% of naldolol in serum is bound to plasma proteins. β-adrenergic receptor antagonists…are well absorbed; some, such as atenolol, sotalol, and naldolol, are poorly lipid-soluble and are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The metabolism of highly lipid-soluble drugs in the liver varies among individuals and may be influenced by age, phenotype, environment, disease, and other drugs, leading to significant fluctuations in plasma concentrations. Liver disease can reduce the clearance of these drugs, but this is generally unaffected by renal insufficiency. All β-adrenergic receptor antagonists reduce cardiac output, which may decrease hepatic clearance of high-extraction drugs. Furthermore, metabolized drugs compete with other drugs for enzymatic biotransformation, making interactions highly likely; however, due to the high therapeutic index of β-adrenergic receptor antagonists, any unexpected clinical response is more likely due to pharmacokinetic alterations of other drugs. In a single-blind, single-dose oral administration of 20 mg naldolol to nine patients scheduled for cataract extraction, intraocular pressure decreased by an average of 24% three hours after administration. Aqueous humor and serum samples were collected intraoperatively to determine naldolol concentrations. Aqueous humor naldolol concentrations ranged from 3.8 to 13.4 ng/mL and were positively correlated with serum drug concentrations (r=0.84). Decreased intraocular pressure was not correlated with naldolol concentrations in aqueous humor or plasma.

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Metabolism/Metabolites
Nardolol is not metabolized by the liver in the human body.
Nardolol is not metabolized.

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Biological Half-Life
The half-life of nalolol is 20 to 24 hours.
The elimination half-life of nalolol is 18 hours. (Data from table)
In patients with normal renal function, the plasma half-life of nalolol is 10-24 hours, and steady-state plasma concentrations are reached in 6-9 days with once-daily dosing. The plasma half-life is prolonged in patients with renal insufficiency.

Hepatotoxicity
In patients taking naldolol, mild to moderate elevations in serum transaminase levels occur in less than 1% of cases and are usually transient and asymptomatic, returning to normal with continued treatment. Despite the widespread use of naldolol, there is no conclusive evidence linking it to clinically significant liver injury; the few reported cases typically occur in patients concurrently taking other known hepatotoxic drugs, or are associated solely with elevated serum enzymes. Other beta-blockers have been thought to be associated with rare cases of acute liver injury with a latency period of 4 to 24 weeks, hepatocellular elevations in serum enzymes, mild and spontaneous course, and no evidence of hypersensitivity or autoimmune reactions. Probability score: E (Unlikely a cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
Because naldolol is largely secreted into breast milk and primarily excreted through the kidneys, other beta-adrenergic blockers should be preferred over naldolol when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
As of the revision date, no published information was found regarding naldolol. A study of mothers taking beta-blockers while breastfeeding found a numerically increased number of adverse events, but this was not statistically significant. Although the infants were age-matched to control groups, the age of affected infants was not specified. None of the mothers were taking naldolol.
◉ Effects on lactation and breast milk
As of the revision date, no published information was found regarding the effects of beta-blockers or naldolol during normal lactation. A study of six patients with hyperprolactinemia and galactorrhea found that serum prolactin levels did not change after β-adrenergic blockade with propranolol. Protein Binding: Nadolol binds to approximately 30% of plasma proteins. It binds to α-1-acid glycoprotein in plasma. Interactions: Nadolol can antagonize the β-adrenergic stimulating effects of sympathomimetic drugs. The interaction between nadolol and isoproterenol is particularly significant, and high doses of isoproterenol may be required to overcome the β-adrenergic blocking effect of nadolol. Antichthyophthirius multifiliis, such as atropine, can counteract the bradycardia caused by nadolol by restoring the balance of cardiac sympathetic and parasympathetic activity. The antihypertensive effect of nadolol may be enhanced when used in combination with diuretics or other antihypertensive drugs. High doses of naldolol may enhance and prolong the effects of neuromuscular blocking agents (such as tubocurarine chloride).

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Non-human toxicity values
Oral LD50 in mice: 4,500 mg/kg
Oral LD50 in rats: 5,300 mg/kg

[1]. Nadolol for Treatment of Supraventricular Tachycardia in Infants and Young Children. Pediatr Cardiol. 2017 Mar;38(3):525-530.

[2]. Role of (-)-Epigallocatechin Gallate in the Pharmacokinetic Interaction Between Nadolol and Green Tea in Healthy Volunteers. Eur J Clin Pharmacol. 2018 Jun;74(6):775-783.

[3]. Effects of Antalarmin and Nadolol on the Relationship Between Social Stress and Pulmonary Metastasis Development in Male OF1 Mice. Behav Brain Res. 2009 Dec 14;205(1):200-6.

Therapeutic Uses
Adrenergic beta-blockers; antiarrhythmics; antihypertensives; sympathomimetic agents. Nadolol can be used alone or in combination with other antihypertensive drugs to treat hypertension. …(Included on US product label) Nadolol has been used in a small number of patients with atrial fibrillation or atrial flutter to treat frequent premature ventricular contractions, paroxysmal atrial tachycardia, and sinus tachycardia, and to lower heart rate. Nadolol has been successfully used in a small number of patients to prevent common migraines. This study reports preliminary data on two key points raised in an earlier report on the efficacy of beta-blockers in treating akathisia: its potential use in the treatment of akathisia in idiopathic Parkinson's disease, and the possibility of determining whether its site of action is central or peripheral by comparing the time course of action of lipophilic and hydrophilic drugs. Four patients with idiopathic Parkinson's disease experienced improvement in akathisia symptoms after receiving low-dose propranolol treatment. Six patients with akathisia caused by antipsychotic medications received treatment with the hydrophilic beta-blocker nadolol. The effect on akathisia improved, but the progression was much slower than with lipophilic drugs (such as propranolol and metoprolol), suggesting that its site of action is in the central nervous system.
For more complete data on the therapeutic uses of nadolol (out of 16), please visit the HSDB record page.

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Drug Warnings
Nardolol is contraindicated in patients with bronchial asthma, sinus bradycardia, first-degree or higher atrioventricular block, cardiogenic shock, or significant heart failure.
Nardolol should be used with caution in patients with impaired renal or hepatic function; patients with impaired renal function may require dose reduction.
Nardolol may mask the symptoms of hyperthyroidism (such as tachycardia); therefore, patients with or suspected of having thyrotoxicosis should be closely monitored, as abrupt discontinuation of beta-adrenergic blockers may induce thyroid storm. Caution is advised for diabetic patients (especially those with unstable blood sugar or prone to hypoglycemia) when using nadolol, as it may mask the signs and symptoms of acute hypoglycemia (such as tachycardia and blood pressure changes, but without sweating). Therefore, diabetic patients receiving hypoglycemic agents, especially those with unstable blood sugar or prone to hypoglycemia, should use nadolol with caution. Beta-adrenergic blockers may also impair glucose tolerance; delay the recovery of blood glucose levels after drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, potentially leading to an overreaction in blood pressure; and may impair peripheral circulation. If diabetic patients are using nadolol concurrently with hypoglycemic agents, the dosage of the hypoglycemic agents may need to be adjusted. A study in non-diabetic patients showed that nadolol treatment did not cause changes in glucose tolerance. Nadolol is excreted into breast milk. Because nadolol may have adverse effects on breastfeeding infants, the importance of the drug to breastfeeding women should be weighed when deciding whether to discontinue breastfeeding or discontinue the medication. For more complete data on naldolol (10 in total), please visit the HSDB records page.

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Pharmacodynamics
Naldolol is a non-selective beta-adrenergic receptor blocker used to lower blood pressure. Because it is usually taken once daily, it has a long duration of action; its therapeutic index is wide because the starting dose is 40 mg daily, but the dose can be increased to 240 mg daily. Patients taking naldolol should not abruptly stop taking it, as this may worsen ischemic heart disease.

C17H27NO4

309.40058

309.194

42200-33-9

Nadolol-d9;94513-92-5

39147

White to off-white solid powder

1.189g/cm3

526.4ºC at 760mmHg

125-130ºC

272.2ºC

1.573

1.025

4

5

6

22

344

2

CC(C)(C)NCC(COC1=CC=CC2=C1C[C@@H]([C@@H](C2)O)O)O

VWPOSFSPZNDTMJ-UCWKZMIHSA-N

InChI=1S/C17H27NO4/c1-17(2,3)18-9-12(19)10-22-16-6-4-5-11-7-14(20)15(21)8-13(11)16/h4-6,12,14-15,18-21H,7-10H2,1-3H3/t12?,14-,15+/m1/s1

(2R,3S)-5-[3-(tert-butylamino)-2-hydroxypropoxy]-1,2,3,4-tetrahydronaphthalene-2,3-diol

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)

DMSO : ~100 mg/mL (~323.21 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.08 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 (8.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (8.08 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.)