(-)-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
Oral doses of nadolol are approximately 30% absorbed. In healthy subjects, nadolol has a Tmax of 2.7h with a Cmax or 69±15ng/mL following a 60mg oral dose and 132±27ng/mL after a 120mg oral dose. The AUC following a 60mg oral dose was 1021ng\*h/mL and following a 120mg oral dose was 1913±382ng\*h/mL.
Nadolol is not metabolized in the liver and excreted mainly in the urine. In healthy subjects, following intravenous dosing, 60% of a dose is eliminated in the urine and 15% in the feces after 72 hours. The remainder of the dose is expected to be eliminated in the feces afterwards.
In healthy subjects, the volume of distribution of nadolol is 147-157L.
In healthy subjects, the total body clearance of nadolol is 219-250mL/min and the renal clearance is 131-150mL/min.
Following oral administration of nadolol, absorption is variable and averages about 30-40% of a dose. The presence of food in the GI tract does not affect the rate or extent of absorption. After oral administration of 2 mg of nadolol (in a capsule), peak plasma concentrations usually occur in 2-4 hours. In one study in hypertensive adults who received 80 mg, 160 mg, or 320 mg of nadolol daily, 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 doses of 40-320 mg daily, the duration of nadolol's antihypertensive and antianginal effects is at least 24 hours.
Following oral administration of 2 mg of radiolabeled nadolol (in a capsule) in one study in patients with normal renal function, about 24.6% and 76.9% of the radioactivity was recovered in urine and feces, respectively, in 4 days.
Nadolol is widely distributed into body tissues. In dogs, minimal amounts of nadolol were detected in the brain and, in rats, the drug crosses the placenta. The drug is distributed into bile. Nadolol is distributed into milk. About 30% of nadolol in serum is bound to plasma proteins.
The beta-adrenoceptor antagonists ... are adequately absorbed, and some like atenolol, sotalol and nadolol which are poorly lipid-soluble are excreted unchanged in the urine, accumulating in renal failure but cleared normally in liver disease. The more lipid-soluble drugs are subject to variable metabolism in the liver, which may be influenced by age, phenotype, environment, disease and other drugs, leading to more variable plasma concentrations. Their clearance is reduced in liver disease but is generally unchanged in renal dysfunction. All the beta-adrenoceptor antagonists reduce cardiac output and this may reduce hepatic clearance of highly extracted drugs. In addition, the metabolised drugs compete with other drugs for enzymatic biotransformation and the potential for interaction is great, but because of the high therapeutic index of beta-adrenoceptor antagonists, any unexpected clinical effects are more likely to be due to changes in the kinetics of the other drug.
Nadolol 20 mg was administered orally as a single-blind, single dose to nine patients about to undergo cataract extraction. Intraocular pressures fell by a mean of 24% 3 hr after administration. During the operation, aqueous humor and serum samples were taken for measurement of nadolol concentrations. Aqueous nadolol concentrations ranged from 3.8 to 13.4 ng/mL, and correlated with the serum drug concentrations (r=0.84). The fall in intraocular pressure did not correlate with either the aqueous humor or plasma concentrations of nadolol.

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Metabolism / Metabolites
Nadolol is not metabolized by the liver in humans.
Nadolol is not metabolized.

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Biological Half-Life
The half life of nadolol is 20 to 24 hours.
The elimination half-life of nadolol is 18 hr. /From table/
In patients with normal renal function, the plasma half-life of nadolol is 10-24 hr and, with once daily doses, steady state is attained in 6-9 days. In patients with renal impairment, plasma half-life is increased.

Hepatotoxicity
Mild-to-moderate elevations in serum aminotransferase levels occur in less than 1% of patients on nadolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its widespread use, nadolol has not been convincingly linked to instances of clinically apparent liver injury; the few cases reported have generally occurred in patients who were receiving other well known hepatotoxic agents or were associated with serum enzyme elevations only. Other beta-blockers have been implicated in causing rare instances of acute liver injury, with latency to onset ranging from 4 to 24 weeks, a hepatocellular pattern of serum enzyme elevations, and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of its relatively extensive excretion into breastmilk and its renal excretion, other beta-adrenergic blocking drugs are preferred to nadolol, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information on nadolol was not found as of the revision date. 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 nadolol.
◉ Effects on Lactation and Breastmilk
Relevant published information on the effects of beta-blockade or nadolol 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
Nadolol is approximately 30% bound to plasma protein. Nadolol binds to alpha-1-acid glycoprotein in plasma.

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Interactions
The beta-adrenergic stimulating effects of sympathomimetic agents are antagonized by nadolol. The interaction is especially pronounced with isoproterenol, and very large doses of isoproterenol may be needed to overcome the beta-adrenergic blocking effects of nadolol.
Antimuscarinic agents, such as atropine, may counteract the bradycardia caused by nadolol by reestablishing the balance between sympathetic and parasympathetic actions on the heart.
When nadolol is administered with diuretics or other hypotensive drugs, the hypotensive effect of nadolol may be increased.
High doses of nadolol may potentiate and prolong the effects of neuromuscular blocking agents such as tubocurarine chloride.

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Non-Human Toxicity Values
LD50 Mouse oral 4,500 mg/kg
LD50 Rat oral 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-Antagonists; Anti-Arrhythmia Agents; Antihypertensive Agents; Sympatholytics
... Nadolol /is/ indicated in the treatment of hypertension when used alone or in combination with other antihypertensive medication. ... /Included in US product labeling/
Nadolol has been used in a limited number of patients with atrial flutter or fibrillation for the management of frequent ventricular premature contractions, paroxysmal atrial tachycardia, and sinus tachycardia and to decrease heart rate. Nadolol has been used with some success in a limited number of patients for the prophylaxis of common migraine headache.
/Exptl/ This investigation reports pilot data on two points originally raised in the earliest reports of the efficacy of beta-blockers in akathisia: their potential utility in the akathisia of idiopathic Parkinson's disease and the possibility of determining a central vs a peripheral site of action by comparing the time course of the effects of lipophilic and hydrophilic agents. Akathisia improved in 4 patients with idiopathic Parkinson's disease after low dose propranolol treatment. Six patients with neuroleptic induced akathisia were treated with the hydrophilic beta-blocker nadolol. Effects on akathisia occurred, but evolved much more slowly than after treatment with lipophilic agents, such as propranolol and metoprolol, thus suggesting a central site of action.
For more Therapeutic Uses (Complete) data for NADOLOL (16 total), please visit the HSDB record page.

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Drug Warnings
Nadolol is contraindicated in patients with bronchial asthma, sinus bradycardia and heart block greater than first degree, cardiogenic shock, or overt cardiac failure.
Nadolol should be used with caution in patients with renal or hepatic impairment, and it may be necessary to reduce the dosage of the drug in those with renal impairment.
Signs of hyperthyroidism (eg, tachycardia) may be masked by nadolol, and patients having or suspected of developing thyrotoxicosis should be monitored closely because abrupt withdrawal of beta-adrenergic blockade might precipitate thyroid storm. It is recommended that nadolol be used with caution in patients with diabetes mellitus (especially those with labile diabetes or those prone to hypoglycemia) since the drug may also mask the signs and symptoms associated with acute hypoglycemia (eg, tachycardia and blood pressure changes but not sweating), the drug should be used with caution in patients with diabetes mellitus receiving hypoglycemic agents, especially in those with labile disease or those prone to hypoglycemia. Beta-adrenergic blocking agents may also impair glucose tolerance; delay the rate of recovery of blood glucose concentration following drug-induced hypoglycemia; alter the hemodynamic response to hypoglycemia, possibly resulting in an exaggerated hypertensive response; and possibly impair peripheral circulation. If nadolol is used in diabetic patients receiving hypoglycemic agents, it may be necessary to adjust the dosage of the hypoglycemic agent. In one study in nondiabetic patients, nadolol therapy did not produce changes in glucose tolerance.
Nadolol is distributed into milk. Because of the potential for adverse reactions to nadolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
For more Drug Warnings (Complete) data for NADOLOL (10 total), please visit the HSDB record page.

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Pharmacodynamics
Nadolol is a nonselective beta adrenal receptor blocker that is used to lower blood pressure. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as patients start at doses of 40mg daily but may be increased to doses as high as 240mg daily. Patients taking nadolol should not aburptly stop taking it as this may lead to exacerbation of 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.)