α1-adrenergic receptor; β-adrenoceptor

Labetalol exhibits a higher affinity for β-primergic sites on guinea pig heart and lung membranes (IC50 values of 0.8 and 4.0 μM, correspondingly)[2]. Labetalol binds to the rabbit uterine membrane's α-primergic binding site. Labctalol's binding affinity to the cardiac membrane's β-binding site is 19 times greater than that of the myocardial membrane's α-binding site [2].

Labetalol (10 mg/kg; ih) passes through the blood-brain barrier and, 90 minutes after injection, reaches tissue levels of 2.1 ug/g in the brains of 10-day-old mice[4]. Labetalol (5.0 mg/kg; ip) Partially inhibits the tailshock stress cascade by circulating IL-1β and IL-6 [5].

Absorption, Distribution and Excretion
After oral administration of 100 mg and 200 mg, the time to peak concentration (Tmax) of labetalol ranges from 20 minutes to 2 hours. Bioavailability may be as low as 11% or as high as 86%, and may be increased in elderly patients or when taken with food. 55-60% of radiolabeled labetalol is recovered in urine, and 12-27% in feces. The volume of distribution is 805 L in normotensive patients. In hypertensive patients, the volume of distribution ranges from 188 to 747 L, with a mean of 392 L. The plasma clearance of labetalol is approximately 1500 mL/min, and the whole blood clearance is 1100 mL/min. Cardiac selective beta-blockers (including labetalol) tend to be hydrophilic, while non-selective beta-blockers tend to be lipophilic. Lipophilicity is an important factor determining their non-selectivity. Lipophilic beta-blockers are typically excreted by the liver and distribute well into all humoral compartments, including the brain. Hydrophilic beta-blockers are typically excreted unchanged by the kidneys and have difficulty penetrating deep humoral compartments. (Data from table)
Beta-blockers are rapidly absorbed, but due to high first-pass liver extraction rates, their bioavailability ranges from 30% to 90%. Most beta-blockers have an apparent volume of distribution greater than 1 liter/kg (class II beta-blockers).
Labetalol hydrochloride is rapidly absorbed from the gastrointestinal tract after oral administration, with an absorption rate of approximately 90-100%, but the drug undergoes extensive first-pass metabolism in the liver and/or gastrointestinal mucosa. After an oral dose in an fasting adult, only about 25% enters the systemic circulation unchanged. While one study reported an absolute bioavailability of 11-86% (mean: 33%) after a single oral dose of 100 mg in fasting adults, the significant inter-individual variability in that study may be due to the use of a relatively low-sensitivity spectrophotometric method. Food delays the gastrointestinal absorption of labetalol hydrochloride but increases its absolute bioavailability, likely by reducing first-pass metabolism and/or hepatic blood flow. In one study, the mean absolute bioavailability of a single oral dose of 200 mg in healthy adults was 26% in fasting and 36% in non-fasting states. First-pass metabolism may be reduced in elderly patients and those with hepatic impairment, resulting in significantly increased bioavailability. However, in a study of patients with hepatosplenic schistosomiasis, the mean absolute bioavailability of the drug was lower compared to healthy individuals. Oral administration of cimetidine increases the bioavailability of labetalol, while glutethimide decreases it. Concomitant oral administration of labetalol hydrochloride and hydrochlorothiazide does not affect the bioavailability of either drug. Following multiple oral doses of labetalol hydrochloride, peak plasma concentrations are typically reached within 40 minutes to 2 hours. It has been reported that peak plasma concentrations increase proportionally with daily oral doses ranging from 100 mg to 3 g. In a study of hypertensive patients, after oral administration of 200 mg labetalol three times daily or 300 mg twice daily, the mean peak plasma concentrations were 323 and 430 ng/ml, respectively, and the mean steady-state plasma drug concentrations were 149 and 145 ng/ml, respectively; these dosing regimens were considered equivalent based on pharmacokinetic and pharmacodynamic (i.e., blood pressure response) assessments. In one study, after intravenous injection of a 1.5 mg/kg dose of labetalol hydrochloride over 1 minute, the mean peak plasma concentration reached approximately 5.7 μg/ml at 2 minutes post-injection and decreased to a mean of 575 ng/ml at 10.5 minutes post-injection. For more complete data on absorption, distribution, and excretion of labetalol (out of 14 studies), please visit the HSDB records page.
Metabolism/Metabolites
The metabolism of labetalol is not fully described in the literature, but sheep studies have shown that it can undergo N-dealkylation to produce 3-amino-1-phenylbutane. This metabolite may be further metabolized to benzylacetone and 3-amino-(4-hydroxyphenyl)butane. In humans, labetalol is primarily metabolized to glucuronide metabolites, such as O-phenylglucuronide and N-glucuronide. After oral administration, labetalol is primarily metabolized in the liver, but may also be metabolized in the gastrointestinal mucosa, mainly through conjugation with glucuronic acid. The main metabolite is O-alkylglucuronide, with small amounts of O-phenylglucuronide and N-glucuronide also produced. After oral administration, labetalol undergoes extensive first-pass metabolism in the liver and/or gastrointestinal mucosa.
Primarily metabolized in the liver, undergoing significant first-pass metabolism.
Elimination pathway: These metabolites are present in plasma and excreted in feces via urine and bile. Half-life: 6–8 hours. Biological half-life: The half-life of labetalol is 1.7–6.1 hours. Plasma concentrations of labetalol appear to decrease in a biphasic or possibly triphasic manner. In healthy and hypertensive adults, the distribution phase half-life has been reported to be 6–44 minutes on average, and the terminal elimination phase half-life (t1/2β) has been reported to be 2.5–8 hours on average. The reported mean half-life of this drug varies, partly because some studies used spectrophotometry, which has relatively low sensitivity. The manufacturer states that the plasma elimination half-life after intravenous or oral administration is 5.5 hours and 6–8 hours, respectively. The elimination half-life appears to be unchanged in patients with impaired renal or hepatic function, but may be prolonged in patients with severe renal impairment (e.g., creatinine clearance less than 10 ml/min) undergoing dialysis; the elimination half-life may also be slightly prolonged in elderly patients (but still within the reported range).

Toxicity Summary
Labetalol has two asymmetric centers and therefore exists as a molecular complex composed of two pairs of diastereomers. The R,R' stereoisomer, delemolol, accounts for 25% of racemic labetalol. Labetalol hydrochloride exhibits both selective competitive α1-adrenergic and non-selective competitive β-adrenergic blocking activities. In humans, the ratio of α- to β-adrenergic blockade is approximately 1:3 after oral administration and 1:7 after intravenous administration. In animal studies, it has been shown to have β2-adrenergic agonist activity, while its β1-adrenergic agonist (ISA) activity is extremely low. In animal studies, membrane-stabilizing effects have been demonstrated at doses higher than those required for α- or β-adrenergic blockade.

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Toxicity Data
LD50 = 66 mg/kg (rat, intravenous injection)

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Interactions
In reproductive studies in rats or rabbits, no evidence of teratogenicity was found at oral doses of labetalol hydrochloride and hydrochlorothiazide, approximately 15 and 80 times the maximum recommended human dose, respectively. However, in rabbits, oral doses of 3.5 and 20 times the maximum recommended human dose, respectively, were maternally toxic and caused fetal toxicity. In rabbits, the toxicity of this combination therapy appears to be higher than that of either drug alone. /Labetalol Hydrochloride/
The antihypertensive effect may be enhanced when labetalol is used in combination with diuretics or other antihypertensive agents. The therapeutic effects and adverse reactions may be additive when β-adrenergic blockers are used concomitantly with calcium channel blockers.

Concurrent intravenous administration of labetalol and halothane anesthesia results in a synergistic hypotensive effect, the extent and duration of which can be controlled by adjusting the halothane concentration; however, excessive hypotension leads to a significant decrease in cardiac output and an increase in central venous pressure.
Studies have shown that oral cimetidine significantly improves the absolute bioavailability of oral labetalol, possibly by enhancing absorption or reducing the first-pass hepatic metabolism of labetalol.
For more complete data on interactions of labetalol (10 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in mice is approximately 0.6 g/kg/labetalol hydrochloride/
Oral LD50 in rats > 2 g/kg/labetalol hydrochloride/
Oral LD50 in dogs > 1 g/kg/labetalol hydrochloride/

[1]. Labetalol: a review of its pharmacology and therapeutic use in hypertension. Drugs. 1978;15(4):251-270.

[2]. Labetalol binding to specific alpha- and beta-adrenergic sites in vitro and its antagonism of adrenergic responses in vivo. J Mol Cell Cardiol. 1979 Aug;11(8):803-11.

[3]. Oral antihypertensive regimens (nifedipine retard, labetalol, and methyldopa) for management of severe hypertension in pregnancy: an open-label, randomised controlled trial. Lancet. 2019 Sep 21;394(10203):1011-1021.

[4]. Changes in adrenoceptors and monoamine metabolism in neonatal and adult rat brain after postnatal exposure to the antihypertensive labetalol. Br J Pharmacol. 1992 Jan;105(1):37-44.

[5]. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience. 2005;135(4):1295-307.

Therapeutic Uses
Adrenergic α-receptor antagonist; Adrenergic β-receptor antagonist; Antihypertensive drug; Sympathomimetic drug
Antihypertensive Drug
Labetalol hydrochloride is an α- and β-adrenergic blocker. It is marketed as a racemic mixture of four stereoisomers. The RR isomer has approximately 2-4 times the β-adrenergic blocking activity of the racemic mixture, but very low α1-adrenergic blocking activity; most of its α1-adrenergic blocking activity is attributed to the SR isomer. The RR isomer also appears to have some β2-adrenergic agonist activity. /Labetalol Hydrochloride/
Labetalol hydrochloride is used to treat hypertension. It can be used alone or in combination with other classes of antihypertensive drugs. Its efficacy is at least comparable to that of pure β-adrenergic blockers, thiazide diuretics, methyldopa, or clonidine. ...Labetalol hydrochloride is administered intravenously to control blood pressure in patients with severe hypertension or hypertensive emergencies. Unlike other currently available parenteral antihypertensive drugs, labetalol typically lowers blood pressure rapidly but slowly without significantly altering heart rate or cardiac output. Intravenous labetalol appears to effectively lower blood pressure in approximately 80-90% of patients with severe hypertension or hypertensive emergencies, regardless of the underlying cause, and may be effective even if other medications are ineffective. /Labetalol Hydrochloride/
For more complete data on the therapeutic uses of labetalol (of 9 types), please visit the HSDB record page.

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Drug Warnings
Serious clinical consequences of overdose primarily affect the cardiovascular system (bradycardia, hypotension, cardiogenic shock, pulmonary edema) and the central nervous system (coma, seizures, respiratory arrest). In cases of severe overdose, sudden respiratory arrest and hemodynamic disturbances may occur after taking a large dose of a beta-blocker. /Class II β-blockers/
Adverse reactions depend more on the drug's affinity for β1 and β2 receptors than on overdose. β1-receptor blocking (antagonist) activity leads to a decrease in sinus rate, contractility, and conduction, reduced renin release, and decreased aqueous humor production. β2-receptor blocking can cause contraction of bronchiolar and arteriolar smooth muscle, reduce insulin secretion, and decrease lipolysis and glycogenolysis, thereby lowering blood levels of fatty acids and glucose. /Class II β-blockers/
Labetalol has similar toxicity to β-adrenergic and postsynaptic α1-adrenergic blockers; therefore, the usual precautions for these drugs should be observed. When labetalol is used in combination with fixed-dose hydrochlorothiazide formulations, in addition to the precautions for labetalol itself, the precautions, contraindications, and adverse reactions of thiazide diuretics must also be considered.
Labetalol should be used with caution in patients with heart failure, as its treatment can block β-adrenergic stimulation, potentially inducing congestive heart failure. Furthermore, prolonged β-adrenergic blockade may lead to heart failure in patients with underlying heart failure. While β-adrenergic blockers should be avoided in patients with marked congestive heart failure, labetalol may be used cautiously in well-compensated heart failure patients (e.g., those controlled with cardiac glycosides and/or diuretics) if necessary. Patients receiving labetalol should be advised to seek immediate medical attention and receive adequate treatment (e.g., with cardiac glycosides and/or diuretics) and close monitoring should they develop signs or symptoms of impending heart failure; if heart failure persists, labetalol should be discontinued, and if possible, gradually phased out.
For more complete data on labetalol (17 in total), please visit the HSDB records page.

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Pharmacodynamics
Labetalol antagonizes multiple adrenergic receptors to lower blood pressure. Because it is usually administered twice daily, it has a long duration of action and a wide therapeutic window; patients typically take 200-400 mg twice daily. Patients prone to bronchospasm should not use labetalol unless they are unresponsive to or intolerant of other antihypertensive drugs.

C19H24N2O3

328.4055

328.178

C, 69.49; H, 7.37; N, 8.53; O, 14.61

36894-69-6

Labetalol hydrochloride; 32780-64-6

3869

White to off-white solid powder

1.2±0.1 g/cm3

552.7±50.0 °C at 760 mmHg

288.1±30.1 °C

0.0±1.6 mmHg at 25°C

1.609

2.31

4

4

8

24

385

0

O([H])C([H])(C1C([H])=C([H])C(=C(C(N([H])[H])=O)C=1[H])O[H])C([H])([H])N([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H]

SGUAFYQXFOLMHL-UHFFFAOYSA-N

InChI=1S/C19H24N2O3/c1-13(7-8-14-5-3-2-4-6-14)21-12-18(23)15-9-10-17(22)16(11-15)19(20)24/h2-6,9-11,13,18,21-23H,7-8,12H2,1H3,(H2,20,24)

2-hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide

Trandate; Labetalol; Normodyne; Apo-Labetalol; Albetol; Dilevalol

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: ~125 mg/mL (~380.6 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.33 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 20.8 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 2: ≥ 2.08 mg/mL (6.33 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 20.8 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.)