Absorption, Distribution and Excretion
It is estimated that the pulmonary bioavailability of formoterol is approximately 43% of the administered dose, while the systemic bioavailability is approximately 60% of the administered dose (because systemic bioavailability includes intestinal absorption). Upon inhalation, formoterol is rapidly absorbed into the plasma. In healthy adults, the time to peak concentration (Tmax) of formoterol ranges from 0.167 to 0.5 hours. After a single 10 μg dose, the peak plasma concentration (Cmax) and area under the curve (AUC) are 22 pmol/L and 81 pmol·h/L, respectively. In adult patients with asthma, the time to peak concentration (Tmax) ranges from 0.58 to 1.97 hours. Following a single 10 μg dose, the peak plasma concentration (Cmax) and area under the curve (AUC0-12h) were 22 pmol/L and 125 pmol·h/L, respectively; after multiple 10 μg doses, Cmax and AUC0-12h were 41 pmol/L and 226 pmol·h/L, respectively. Within the standard dose range, absorption appears to be dose-proportional. Drug elimination varies depending on the route of administration and formulation. In two healthy subjects, approximately 59–62% and 32–34% of the administered dose were excreted in the urine and feces, respectively, after oral administration. Another study attempting to simulate inhalation through combined intravenous/oral administration found that approximately 62% of the administered dose was excreted in the urine and 24% in the feces. In asthmatic patients, approximately 10% and 15-18% of the administered dose are excreted in the urine as unchanged drug and direct formoterol glucuronide, respectively; the corresponding values for patients with chronic obstructive pulmonary disease (COPD) are 7% and 6-9%, respectively. The renal clearance of formoterol after inhalation is approximately 157 mL/min. Protein binding: moderate, 61-64%. Serum albumin binding is 31%-38% in the range of 5-500 ng/mL. Bioavailability: pulmonary: 21-37%; systemic: 46%. It is unclear whether formoterol is distributed in human milk. However, after oral administration, it is distributed in rat milk. In asthmatic patients, 10% and 15-18% of the drug are excreted in the urine as unchanged drug, respectively, after administration of 12 or 24 μg doses. In patients with chronic obstructive pulmonary disease (COPD), 7% and 6% to 9% of the drug, respectively, are excreted unchanged in the urine after taking 12 or 24 mcg doses. For more complete data on the absorption, distribution, and excretion of formoterol (8 metabolites), please visit the HSDB record page. Metabolites/Metabolites Formoterol is primarily metabolized via direct glucuronidation of the parent drug and subsequent glucuronidation following O-demethylation of the parent drug. Secondary metabolic pathways include sulfate conjugation of the parent drug and subsequent sulfate conjugation following deformylation of the parent drug, but these secondary metabolic pathways are not fully elucidated. The primary metabolic pathway of formoterol is direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second primary pathway is O-demethylation followed by glucuronidation at the phenolic hydroxyl group. In vitro studies have shown that the metabolic pathways of formoterol include: O-demethylation involving multiple cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6), and glucuronidation involving multiple UDP-glucuronyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), but the specific roles of these enzymes remain unclear. Formoterol is primarily metabolized via direct glucuronidation of phenolic or aliphatic hydroxyl groups and glucuronide binding to the phenolic hydroxyl group after O-demethylation. Secondary metabolic pathways include sulfate binding of formoterol and sulfate binding after deformylation. The most important metabolic pathway is the direct binding of the phenolic hydroxyl group. The second major pathway involves initial O-demethylation followed by binding to the 2'-hydroxyl group of the phenolic hydroxyl group. Four cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) are involved in the O-demethylation of formoterol. At treatment-related concentrations, formoterol does not inhibit CYP450 enzymes. Some patients may have a deficiency of CYP2D6 or CYP2C19, or both. It has not been sufficiently investigated whether a deficiency of one or both of these isoenzymes leads to increased systemic exposure to formoterol or systemic adverse reactions. Formoterol can bind to an inactive glucuronide and a previously unidentified sulfate. Phenolic glucuronide of formoterol is the major metabolite in urine. Formoterol also undergoes O-demethylation and deformylation. Plasma exposure to these pharmacologically active metabolites is low. O-demethylated formoterol exists primarily as an inactive glucuronide conjugate, while deformylated formoterol exists only as an inactive sulfate conjugate. Formoterol recovered in feces was primarily intact formoterol and O-demethylated formoterol. The mean recovery rate of unidentified metabolites in urine was 7.0%, and in feces, it was 2.0%. Biological Half-Life Following inhalation of formoterol, the mean terminal elimination half-life is 7–10 hours, depending on the formulation. After oral administration, the estimated plasma half-life of formoterol is 3.4 hours; after inhalation, the estimated plasma half-life is 1.7–2.3 hours. Mean Terminal Half-Life: 10 hours

Effects During Pregnancy and Lactation
◉ Overview of Lactation Use
While there is currently no published data on the use of inhaled formoterol during lactation, data on the related drug terbutaline suggest that only a very small amount of the drug is expected to be excreted into breast milk. Authors of multiple reviews and expert guidelines agree that the use of such drugs during lactation is acceptable due to the low bioavailability of inhaled bronchodilators and the low maternal serum concentrations after administration.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.
◈ What is Formoterol?
Formoterol (also known as ivomoterol) is a medication used to treat asthma and chronic obstructive pulmonary disease (COPD). It belongs to the long-acting β2-agonist (LABA) class of drugs. LABA is a bronchodilator that helps dilate the airways in the lungs. Formoterol is administered via inhalation. It has been used in combination with inhaled corticosteroids to treat asthma. For information on inhaled corticosteroids, see the relevant information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/inhaled-corticosteroids-icss-pregnancy/. Some brand names for formoterol include Foradil®, Perforomist®, and Brovana®. Formoterol is also found in some combination medications, such as Symbicort® and Dulera®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or stopping it entirely. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating the condition during pregnancy. Poorly controlled asthma increases the risks of pregnancy. For more information, see our asthma condition sheet: https://mothertobaby.org/fact-sheets/asthma-and-pregnancy/.
◈ I am taking formoterol. Will it make it harder for me to get pregnant?
It is currently unclear whether formoterol makes it harder to get pregnant.
◈ Does taking formoterol increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There is currently no research indicating that formoterol increases the risk of miscarriage.
◈ Does taking formoterol increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy. This is called background risk. Data on the use of formoterol during pregnancy is limited. Existing animal studies and human case reports suggest that the use of formoterol during pregnancy does not increase the risk of birth defects. One study on the overall use of long-acting β2-adrenergic receptor agonists (LABAs) reported that use of LABAs in early pregnancy increased the risk of fetal heart defects. However, it is currently unclear whether these birth defects are caused by the drug itself, the disease being treated, or other factors.
◈ Does taking formoterol during pregnancy increase the risk of other pregnancy-related problems?
A report on 33 pregnant women who used formoterol during pregnancy described 5 cases of preterm birth (delivery before 37 weeks of gestation). Another study compared 162 pregnancies using formoterol with those using another long-acting β2-agonist (LABA), finding no difference between the two groups in terms of birth weight, gestational age, or risk of preterm birth. Poor asthma control during pregnancy is associated with a higher incidence of pregnancy complications, such as preterm birth, low birth weight, and other complications.
◈ Will taking formoterol during pregnancy affect a child's future behavior or learning abilities?
Based on the reviewed studies, it is unclear whether formoterol increases the risk of behavioral or learning problems in children.
◈ Breastfeeding while taking formoterol:
There are currently no studies on the use of formoterol while breastfeeding. Information about the drug suggests that using a formoterol inhaler is unlikely to result in excessively high blood concentrations that would pass into breast milk. Inhaled bronchodilators are generally considered safe for use during breastfeeding. Please consult your healthcare provider with any questions regarding breastfeeding.
◈ If a man takes formoterol, will it affect his fertility (the ability to impregnate his partner) or increase the risk of birth defects?
Currently, no studies have explored whether formoterol affects male fertility or increases the risk of birth defects (above background risk). Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please refer to the "Fatherly Contact" information on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
The binding rate of plasma proteins to serum albumin in vitro is approximately 31%-38%, with plasma concentrations ranging from 5-500 ng/mL. However, it should be noted that these concentrations are higher than those after inhalation.

(S,S)-Formoterol is an N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propyl-2-yl]amino}ethyl)phenyl]formamide, wherein both stereocenters are in the S configuration. It is the conjugate base of (S,S)-formoterol(1+) and the enantiomer of aformoterol. Formoterol is an inhaled β2-receptor agonist used to treat chronic obstructive pulmonary disease (COPD) and asthma, and was first approved for marketing in the United States in 2001. It acts on bronchial smooth muscle, dilating and relaxing the airways, and is usually administered as a racemic mixture of its active (R;R)-enantiomer and inactive (S;S)-enantiomer. The main clinical advantage of formoterol over other inhaled β-receptor agonists is its rapid onset of action (2-3 minutes), at least as fast as salbutamol, and its long duration of action (12 hours). Therefore, asthma treatment guidelines recommend it as a reliever and maintenance therapy. Formoterol is available as a single-agent formulation or in combination with inhaled corticosteroids and long-acting muscarinic receptor antagonists. Formoterol is a long-acting β-adrenergic receptor agonist with bronchodilatory effects. Formoterol selectively binds to β2-adrenergic receptors in bronchial smooth muscle, thereby activating intracellular adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Elevated cAMP levels lead to bronchial smooth muscle relaxation, relieve bronchospasm, improve mucociliary clearance, and reduce mediators released by inflammatory cells, particularly mast cells. A long-acting β2-adrenergic receptor agonist. Used to treat asthma and chronic obstructive pulmonary disease (COPD). See also: Formoterol (note moved to).

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Drug Indications
Formoterol is available in various formulations for the treatment of asthma and COPD. In the treatment of chronic obstructive pulmonary disease (COPD), formoterol can be used as a single inhaled solution, or in combination with long-acting muscarinic receptor antagonists (LAMAs) [acrylidine] and [glycopyrronium bromide], or with the corticosteroid [budesonide]. For the treatment of asthma, formoterol can be used in combination with mometasone furoate in patients 5 years of age and older, and with budesonide in patients 6 years of age and older. Formoterol can also be used as needed to prevent exercise-induced bronchospasm.
FDA Label

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Mechanism of Action
Formoterol is a relatively selective, long-acting β2-adrenergic receptor agonist, although it also has some activity against β1 and β3 receptors. β2 receptors are primarily found in bronchial smooth muscle (with relatively low concentrations in cardiac tissue), while β1 receptors are the main adrenergic receptors in the heart. Therefore, selective action against β2 receptors is crucial in the treatment of lung diseases such as COPD and asthma. Formoterol exhibits approximately 200 times greater activity against β2 receptors than against β1 receptors. At the molecular level, agonists like formoterol activate β receptors, stimulating the activity of intracellular adenylate cyclase, an enzyme responsible for converting ATP to cyclic adenosine monophosphate (cAMP). Elevated cAMP levels in bronchial smooth muscle tissue lead to muscle relaxation, thereby dilating the airways and inhibiting the release of allergic mediators (such as histamine and leukotrienes) from sensitized cells, particularly mast cells. Formoterol is a long-acting, selective β2-adrenergic receptor agonist of bronchial smooth muscle. This stimulation relaxes smooth muscle fibers, resulting in bronchodilatory effects. Formoterol stimulates β2-adrenergic receptors but has little effect on β1- or α-adrenergic receptors. The drug's β-adrenergic effect appears to be achieved by activating adenylate cyclase to stimulate the production of cyclic adenosine monophosphate (cAMP). Cyclic adenosine monophosphate mediates a variety of cellular responses, and elevated cAMP concentrations are associated with bronchial smooth muscle relaxation and inhibition of certain aspects of inflammation, such as the inhibition of the release of pro-inflammatory mast cell mediators (such as histamine and leukotrienes).

C19H24N2O4

344.411

344.173

67346-48-9

Formoterol fumarate;43229-80-7;Arformoterol;67346-49-0;Arformoterol maleate;1254575-18-2

3034756

Typically exists as solid at room temperature

1.2±0.1 g/cm3

603.2±55.0 °C at 760 mmHg

318.6±31.5 °C

0.0±1.8 mmHg at 25°C

1.617

1.57

4

5

8

25

388

2

O[C@@H](C1C=CC(=C(C=1)NC=O)O)CN[C@@H](C)CC1C=CC(=CC=1)OC

BPZSYCZIITTYBL-ORAYPTAESA-N

InChI=1S/C19H24N2O4/c1-13(9-14-3-6-16(25-2)7-4-14)20-11-19(24)15-5-8-18(23)17(10-15)21-12-22/h3-8,10,12-13,19-20,23-24H,9,11H2,1-2H3,(H,21,22)/t13-,19+/m0/s1

N-[2-hydroxy-5-[(1S)-1-hydroxy-2-[[(2S)-1-(4-methoxyphenyl)propan-2-yl]amino]ethyl]phenyl]formamide

Foradil (S,S)-Formoterol (+)-Formoterol

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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