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.
◉ 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 an expert panel 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 used for the treatment of asthma and chronic obstructive pulmonary disease (COPD). It is in a class of medications called long-acting beta2-agonists. Beta2-agonists are bronchodilators. Bronchodilators help to open the airways in the lungs. Formoterol is taken by inhalation (breathing it in). It is usually 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/pdf/. Formoterol can be found in some combination medications such as Symbicort® and Dulera®.
◈ I take formoterol. Can it make it harder for me to get pregnant?
Studies have not been done to see if formoterol could make it harder for a woman to get pregnant.
◈ I just found out that I am pregnant. Should I stop using my formoterol inhaler?
Talk with your healthcare providers before making any changes to your medication(s). It is important to consider the benefits of controlling asthma symptoms during pregnancy. Untreated asthma increases the chance for complications for both the pregnant woman and the baby. For more information about asthma, please see the MotherToBaby fact sheet at https://mothertobaby.org/fact-sheets/asthma-and-pregnancy/pdf/.If a woman’s asthma is well-controlled with formoterol prior to pregnancy, it is considered appropriate to continue its use during pregnancy if needed. When formoterol is inhaled, very limited amounts of the drug enter the blood, and even less is thought to reach the developing baby.
◈ Does taking formoterol increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. There are no published studies looking at whether formoterol increases the chance of miscarriage.
◈ Can taking formoterol increase the chance of birth defects?
In every pregnancy, a woman starts out with a 3-5% chance of having a baby with a birth defect. This is called her background risk.There is limited data on the use of formoterol during pregnancy. The information from case reports did not suggest an increased chance of harm. A study on the use of long acting beta2-agonists (LABA) reported an increased chance for heart defects when used in the first trimester. However, these results are not conclusive since the pregnant woman’s underlying condition and severity of her asthma symptoms could have influenced the results. While more data is needed on formoterol, it is commonly used during pregnancy in combination with inhaled corticosteroids when asthma symptoms are severe enough to require treatment.
◈ Can taking formoterol during pregnancy cause other pregnancy complications?
One report of 33 women who used formoterol during pregnancy described five cases of birth before 37 weeks of pregnancy (preterm delivery). Three cases of preterm delivery would be expected due to the background risk. Another study compared 162 formoterol-exposed pregnancies to another long acting beta agonist and did not find a difference in birth weight, gestational age or chance of preterm delivery. It is unlikely that the chance for preterm delivery was increased by the use of formoterol during pregnancy. There may be a relationship between preterm delivery and poorly controlled or more severe asthma in pregnancy.
◈ Does taking formoterol in pregnancy cause long-term problems in behavior or learning for the baby?
There are not enough studies on formoterol to know whether there is a chance for long-term problems.
◈ Can I take formoterol while breastfeeding?
There have not been any studies on women taking formoterol while breastfeeding. Information on the use of related medications suggest that the use of a formoterol inhaler would be unlikely to result in high enough levels in the woman’s 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 man takes formoterol, could it affect his fertility (ability to get partner pregnant) or increase the chance of birth defects?
There are no data to suggest a man’s use of formoterol at the time of conception increases the chance for infertility or birth defects. In general, exposures that fathers have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/pdf/.
Concomitant treatment /with monoamine oxidase inhibitors, including furazolidine and procarbazine/ may prolong the QTc interval and increase the risk of ventricular arrhythmias; may increase chance of hypertensive reactions.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
可能会增加接受卤代烃类麻醉药患者的心律失常风险。
May increase risk of arrhythmias in patients receiving halogenated hydrocarbon anesthesia.
Concomitant treatment /with tricyclic antidepressants, disopyramide, phenothiazines, procainamide or quinidine/may prolong the QTc interval and increase the risk of ventricular arrhythmias.
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.
来源:DrugBank
吸收、分配和排泄
清除
吸入后福莫特罗的肾清除率大约为157毫升/分钟。
Renal clearance of formoterol following inhalation is approximately 157 mL/min.
Understanding Flavin-Dependent Halogenase Reactivity via Substrate Activity Profiling
摘要：
The activity of four native FDHs and four engineered FDH variants on 93 low-molecular-weight arenes was used to generate FDH substrate activity profiles. These profiles provided insights into how substrate class, functional group substitution, electronic activation, and binding affect FDH activity and selectivity. The enzymes studied could halogenate a far greater range of substrates than have been previously recognized, but significant differences in their substrate specificity and selectivity were observed. Trends between the electronic activation of each site on a substrate and halogenation conversion at that site were established, and these data, combined with docking simulations, suggest that substrate binding can override electronic activation even on compounds differing appreciably from native substrates. These findings provide a useful framework for understanding and exploiting FDH reactivity for organic synthesis.
SMALL MOLECULE ENTEROVIRUS INHIBITORS AND USES THEREOF
申请人：Arizona Board of Regents on Behalf of the University of Arizona
公开号：US20210244721A1
公开（公告）日：2021-08-12
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinoline (or similar) structure which function as antagonists of androgen receptor activity, and their use as therapeutics for the treatment of cancer (e.g., castration-resistant prostate cancer) and other conditions characterized with androgen receptor activity and/or androgen receptor expression.
PURIFICATION PROCESS FOR PREPARING HIGHLY PURE ARFORMOTEROL TARTRATE SUBSTANTIALLY FREE OF DESFORMYL IMPURITY
申请人：Jagtap Anant Kishanrao
公开号：US20120053246A1
公开（公告）日：2012-03-01
Provided herein is a highly pure arformoterol tartrate or an amorphous form thereof substantially free of desformyl impurity, 2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]aniline, process for the preparation thereof, and pharmaceutical compositions comprising the highly pure arformoterol tartrate substantially free of the desformyl impurity.
[EN] COMPOSITIONS AND METHODS OF REGULATING CANCER RELATED DISORDERS AND DISEASES<br/>[FR] COMPOSITIONS ET MÉTHODES DE RÉGULATION DE TROUBLES ET MALADIES ASSOCIÉS AU CANCER
申请人：ONCO THERAPIES LLC
公开号：WO2017070052A1
公开（公告）日：2017-04-27
Provided herein are naphthylic derivative compounds, or pharmaceutically acceptable salts thereof, that are useful for inhibiting cancers. Also provided herein are methods of using effective amounts of said compounds, optionally with pharmaceutical carriers, for the treatment of cancers within human subjects.
PROCESSES FOR PREPARING SUBSTANTIALLY PURE ARFORMOTEROL AND ITS INTERMEDIATES
申请人：Dixit Girish
公开号：US20110313199A1
公开（公告）日：2011-12-22
Provided herein are improved, convenient and industrially advantageous processes for the preparation of N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide (Arformoterol) or a pharmaceutically acceptable salt thereof, in high yield and purity. Provided further herein is an improved and industrially advantageous process for the preparation of a substantially enantiomerically pure arformoterol intermediate, (R)-4-methoxy-α-methyl-N-(phenylmethyl)benzeneethanamine.
[EN] BUDESONIDE 21-PHOSPHATE SALTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME<br/>[FR] SELS DE BUDÉSONIDE 21-PHOSPHATE ET COMPOSITIONS PHARMACEUTIQUES LES CONTENANT
申请人：GENETIC S P A
公开号：WO2021191366A1
公开（公告）日：2021-09-30
The present invention relates to salts of budesonide 21-phosphate with β2 adrenergic agonists, preferably with formoterol, pharmaceutical compositions containing the same and the use thereof in the treatment of respiratory inflammatory pathologies, obstructive pathologies and allergen-induced airway dysfunctions. The invention further relates to the process for preparing said salts.
