Absorption, Distribution and Excretion
The pulmonary bioavailability of formoterol has been estimated to be about 43% of the delivered dose, while the total systemic bioavailability is approximately 60% of the delivered dose (as systemic bioavailability accounts for absorption in the gut). Formoterol is rapidly absorbed into plasma following inhalation. In healthy adults, formoterol Tmax ranged from 0.167 to 0.5 hours. Following a single dose of 10 mcg, Cmax and AUC were 22 pmol/L and 81 pmol.h/L, respectively. In asthmatic adult patients, Tmax ranged from 0.58 to 1.97 hours. Following single-dose administration of 10mcg, Cmax and AUC0-12h were 22 pmol/L and 125 pmol.h/L, respectively; following multiple-dose administration of 10 mcg, Cmax and AUC0-12h were 41 pmol/L and 226 pmol.h/L, respectively. Absorption appears to be proportional to dose across standard dosing ranges.
Elimination differs depending on the route and formulation administered. Following oral administration in 2 healthy subjects, approximately 59-62% and 32-34% of an administered dose was eliminated in the urine and feces, respectively. Another study which attempted to mimic inhalation via combined intravenous/oral administration noted approximately 62% of the administered dose in the urine and 24% in the feces. Following inhalation in patients with asthma, approximately 10% and 15-18% of the administered dose was excreted in urine as unchanged parent drug and direct formoterol glucuronides, respectively, and corresponding values in patients with COPD were 7% and 6-9%, respectively.
Renal clearance of formoterol following inhalation is approximately 157 mL/min.
Protein binding: Moderate 61-64%. Serum albumin binding was 31% to 38% over a range of 5 to 500 ng/mL.
Bioavailability: Pulmonary: 21-37%; Total systemic: 46%.
It is not known whether formoterol is distributed in human breast milk. However, it is distributed in rat milk after oral administration.
In asthma patients following a 12 or 24 ug dose: 10% and 15 to 18% excreted unchanged in the urine, respectively. In chronic obstructive pulmonary disease (COPD) patients following a 12 or 24 ug dose: 7% and 6 to 9% excreted unchanged in the urine; respectively.
For more Absorption, Distribution and Excretion (Complete) data for FORMOTEROL (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Formoterol is metabolized primarily via direct glucuronidation of the parent drug and via O-demethylation of the parent drug followed by glucuronidation. Minor pathways include sulfate conjugation of the parent drug and deformylation of the parent drug followed by sulfate conjugation, though these minor pathways have not been fully characterized. The major pathway of formoterol metabolism is a direct glucuronidation of the parent drug at its phenolic hydroxyl group, while the second most prominent pathway involves O-demethylation following by glucuronidation at the phenolic hydroxyl group. _In vitro_ studies of formoterol disposition indicate that O-demethylation of formoterol involves a number of cytochrome P450 isoenzymes (CYP2D6, CYP2C19, CYP2C9, and CYP2A6) and glucuronidation involves a number of UDP-glucuronosyltransferase isoenzymes (UGT1A1, UGT1A8, UGT1A9, UGT2B7, and UGT2B15), though specific roles for individual enzymes have not been elucidated.
Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.
Formoterol was conjugated to inactive glucuronides and a previously unidentified sulfate. The phenol glucuronide of formoterol was the main metabolite in urine. Formoterol was also O-demethylated and deformylated. Plasma exposure to these pharmacologically active metabolites was low. O-demethylated formoterol was seen mainly as inactive glucuronide conjugates and deformylated formoterol only as an inactive sulfate conjugate. Intact formoterol and O-demethylated formoterol dominated recovery in feces. Mean recovery of unidentified metabolites was 7. 0% in urine and 2.0% in feces.

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Biological Half-Life
The average terminal elimination half-life of formoterol following inhalation is 7-10 hours, depending on the formulation given. The plasma half-life of formoterol has been estimated to be 3.4 hours following oral administration and 1.7-2.3 hours following inhalation.
Mean terminal: 10 hours

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Although no published data exist on the use of formoterol by inhaler during lactation, data from the related drug, terbutaline, indicate that very little is expected to be excreted into breastmilk. The authors of several reviews and expert guidelines agree that use of inhaled bronchodilators is acceptable during breastfeeding because of the low bioavailability and maternal serum levels after use.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.
◈ What is formoterol?
Formoterol (also called eformoterol) is a medication that has been used to treat asthma and chronic obstructive pulmonary disease (COPD). It is in a class of medications called long-acting beta2-agonists (LABAs). LABAs are bronchodilators. Bronchodilators help open the airways in the lungs. Formoterol is taken by inhalation (breathing it in). It has been used in combination with an inhaled corticosteroid for asthma treatment. For information about inhaled corticosteroids, see the MotherToBaby fact sheet at https://mothertobaby.org/fact-sheets/inhaled-corticosteroids-icss-pregnancy/. Some brand names of formoterol are Foradil®, Perforomist®, and Brovana®. Formoterol can also be found in some combination medications such as Symbicort® and Dulera®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy. Asthma that is not well-controlled can increase risks to a pregnancy. For more information, see our fact sheet on asthma here https://mothertobaby.org/fact-sheets/asthma-and-pregnancy/.
◈ I take formoterol. Can it make it harder for me to get pregnant?
It is not known if formoterol can make it harder to get pregnant.
◈ Does taking formoterol increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if formoterol increases the chance for miscarriage.
◈ Does taking formoterol increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk.There is limited data on the use of formoterol during pregnancy. Available information from animal studies and human case reports does not suggest an increased chance of birth defects when formoterol is used in pregnancy.A study on the use of LABAs as a group reported an increased chance for heart defects when used in the first trimester. However, it is not known if the medication, the condition being treated, or other factors caused the reported birth defects.
◈ Does taking formoterol in pregnancy increase the chance of other pregnancy-related problems?
One report of 33 people who used formoterol during pregnancy described 5 cases of preterm delivery (birth before week 37). Another study compared 162 formoterol-exposed pregnancies to another LABA and did not find a difference in birth weight, gestational age, or chance of preterm delivery.Asthma that is not well-controlled during pregnancy is associated with higher rates of pregnancy complications such as preterm delivery, low birth weight, and other complications.
◈ Does taking formoterol in pregnancy affect future behavior or learning for the child?
Based on the studies reviewed, it is not known if formoterol increases the chance for behavior or learning issues.
◈ Breastfeeding while taking formoterol:
There are no studies on the use of formoterol while breastfeeding. Information on related medications suggests that use of a formoterol inhaler would be unlikely to result in high enough levels in the bloodstream to pass into breast milk in large amounts. Inhaled bronchodilators are generally considered acceptable for use during breastfeeding. Be sure to talk to your healthcare provider about all of your breastfeeding questions.
◈ If a male takes formoterol, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done to see if formoterol could affect male fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Protein Binding
Plasma protein binding to serum albumin _in vitro_ is approximately 31%-38% over a plasma concentration range of 5-500 ng/mL - it should be noted, however, that these concentrations are higher than that seen following inhalation.

(S,S)-formoterol is an N-[2-hydroxy-5-(1-hydroxy-2-{[1-(4-methoxyphenyl)propan-2-yl]amino}ethyl)phenyl]formamide in which both of the stereocentres have S configuration. It is a conjugate base of a (S,S)-formoterol(1+). It is an enantiomer of an arformoterol.
Formoterol is an inhaled beta2-agonist used in the management of COPD and asthma that was first approved for use in the United States in 2001. It acts on bronchial smooth muscle to dilate and relax airways, and is administered as a racemic mixture of its active (R;R)- and inactive (S;S)-enantiomers. A major clinical advantage of formoterol over other inhaled beta-agonists is its rapid onset of action (2-3 minutes), which is at least as fast as [salbutamol], combined with a long duration of action (12 hours) - for this reason, treatment guidelines for asthma recommend its use as both a reliever and maintenance medication. It is available as a single-entity product and in several formulations in combination with both inhaled corticosteroids and long-acting muscarinic antagonists.
Formoterol is a long-acting beta-adrenergic receptor agonist with bronchodilator activity. Formoterol selectively binds to beta-2 adrenergic receptors in bronchial smooth muscle, thereby activating intracellular adenyl cyclase, an enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle, relieve bronchospasms, improve mucociliary clearance and reduce mediator substance release from inflammatory cells, especially from mast cells.
An ADRENERGIC BETA-2 RECEPTOR AGONIST with a prolonged duration of action. It is used to manage ASTHMA and in the treatment of CHRONIC OBSTRUCTIVE PULMONARY DISEASE.
See also: Formoterol (annotation moved to).

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Drug Indication
Formoterol is indicated in various formulations for the treatment of asthma and COPD. For the treatment of COPD, formoterol is available as a single-entity inhalation solution, in combination with the long-acting muscarinic antagonists (LAMAs) [aclidinium] and [glycopyrronium], and in combination with the corticosteroid [budesonide]. For the treatment of asthma, formoterol is available in combination with [mometasone furoate] for patients 5 years and older and with budesonide for patients 6 years and older. Formoterol may also be used on an as-needed basis for prophylaxis against exercise-induced bronchospasm.
FDA Label

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Mechanism of Action
Formoterol is a relatively selective long-acting agonist of beta₂-adrenergic receptors, although it does carry some degree of activity at beta₁ and beta₃ receptors. Beta₂ receptors are found predominantly in bronchial smooth muscle (with a relatively minor amount found in cardiac tissue) whereas beta₁ receptors are the predominant adrenergic receptors found in the heart - for this reason, selectivity for beta₂ receptors is desirable in the treatment of pulmonary diseases such as COPD and asthma. Formoterol has demonstrated an approximately 200-fold greater activity at beta₂ receptors over beta₁ receptors. On a molecular level, activation of beta receptors by agonists like formoterol stimulates intracellular adenylyl cyclase, an enzyme responsible for the conversion of ATP to cyclic AMP (cAMP). The increased levels of cAMP in bronchial smooth muscle tissue result in relaxation of these muscles and subsequent dilation of the airways, as well as inhibition of the release of hypersensitivity mediators (e.g. histamine, leukotrienes) from culprit cells, especially mast cells.
Formoterol is a long-acting selective stimulator of the beta2-adrenergic receptors in bronchial smooth muscle. This stimulation causes relaxation of smooth muscle fibers and produces bronchodilation.
Formoterol stimulates beta2-adrenergic receptors and apparently has little or no effect on beta1- or alpha-adrenergic receptors. The drug's beta-adrenergic effects appear to result from stimulation of the production of cyclic adeno-3'-5'-monophosphate (cAMP)by activation of adenyl cyclase. Cyclic AMP mediate numerous cellular responses, increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle and suppression of some aspects of inflammation, such as inhibition of release proinflammatory mast cell mediators(eg histamine, 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.)