Umeclidinium

Identification

Summary

Umeclidinium is a long-acting muscarinic antagonist used as a long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

Brand Names
Anoro, Anoro Ellipta, Incruse Ellipta, Trelegy Ellipta
Generic Name
Umeclidinium
DrugBank Accession Number
DB09076
Background

Umeclidinium is a long-acting muscarinic antagonist (LAMA) used as a maintenance treatment for symptoms of chronic obstructive pulmonary disease (COPD). COPD is a progressive obstructive lung disease characterized by shortness of breath, cough, sputum production, and chronically poor airflow with a forced expiratory volume in 1 second (FEV1) of less than 80%.3

Maintenance of the airway is controlled by the parasympathetic nervous system, particularly by the abundance of the muscarinic subtype 3 (M3) in the airway smooth muscle.5 Parasympathetic ganglia are associated with the larger airways while postganglionic fibers innervate the smaller diameter bronchioles contributing to airway resistance.5 By blocking the M3 muscarinic receptor, umeclidinium inhibits the binding of acetylcholine and thereby opens up the airways by preventing bronchoconstriction.5 However, even though umeclidinium monotherapy is well-tolerated for up to 14 days, it is more likely to be used in combination therapy, as the international Gold Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommended the use of two long-acting bronchodilators with differing mechanisms of action to maximize efficacy and minimize adverse effects.4,2

Umeclidinium was approved by the FDA in April 2014 under the brand name Incruse Ellipta as a standalone product.14 Later, it was further approved as a combination product with vilanterol and vilanterol/fluticasone furoate under the brand name ANORO ELLIPTA and TRELEGY ELLIPTA respectively.9,10. ANORO ELLIPTA was approved in December 2013 while TRELEGY ELLIPTA was approved in September 2017.15,16

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 428.595
Monoisotopic: 428.258405759
Chemical Formula
C29H34NO2
Synonyms
  • 1-[2-(benzyloxy)ethyl]-4-[hydroxy(diphenyl)methyl]-1-azoniabicyclo[2.2.2]octane
  • Umeclidinium
External IDs
  • GSK-573719
  • GSK573719
  • GSK573719A

Pharmacology

Indication

Umeclidinium is approved by the FDA and Health Canada for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).7,8 Additionally, umeclidinium also exists as combination products with vilanterol or vilanterol and fluticasone furoate.9,10,12,13 Both products were indicated for the maintenance treatment of COPD, but only the umeclidinium/vilanterol/fluticasone furoate product was approved for the maintenance treatment of asthma in patients aged 18 years and older.9,10,12,13

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to manageAsthmaCombination Product in combination with: Fluticasone furoate (DB08906), Vilanterol (DB09082)••••••••••••••••••
Used in combination to manageAsthmaCombination Product in combination with: Fluticasone furoate (DB08906), Vilanterol (DB09082)••••••••••••••••••
Used in combination to manageChronic obstructive pulmonary diseaseCombination Product in combination with: Vilanterol (DB09082), Fluticasone furoate (DB08906)••••••••••••••••••
Used in combination to manageChronic obstructive pulmonary diseaseCombination Product in combination with: Vilanterol (DB09082)••••••••••••••••••
Used in combination to manageChronic obstructive pulmonary diseaseCombination Product in combination with: Vilanterol (DB09082)••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent.7

In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca2+.6 Increase in intracellular Ca2+ results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction.6 Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca2+ homeostasis that will lead to muscle contraction.6

Mechanism of action

Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect.7

TargetActionsOrganism
AMuscarinic acetylcholine receptor M3
antagonist
Humans
UMuscarinic acetylcholine receptor M2
antagonist
Humans
UMuscarinic acetylcholine receptor M1
antagonist
Humans
UMuscarinic acetylcholine receptor M4
antagonist
Humans
UMuscarinic acetylcholine receptor M5
antagonist
Humans
Absorption

Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation.7 The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral absorption.8

Volume of distribution

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L.7

Protein binding

In vitro plasma protein binding in human plasma was on average 89%.7

Metabolism

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.7

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Route of elimination

Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption.7

Half-life

The effective half-life after once-daily inhaled dosing is 11 hours.7

Clearance

Plasma clearance following intravenous administration was 151 L/hour.8

Adverse Effects
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Toxicity

In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the maximum recommended human daily inhaled dose (MRHDID), respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species.7

In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day).7

Based on available data, no adjustment of the dosage of umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.7

Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).7

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.7

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).7

No human overdosage data has been reported with umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg of umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy.7

In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbataceptThe metabolism of Umeclidinium can be increased when combined with Abatacept.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Umeclidinium.
AbirateroneThe metabolism of Umeclidinium can be decreased when combined with Abiraterone.
AbrocitinibThe serum concentration of Umeclidinium can be increased when it is combined with Abrocitinib.
AcebutololThe metabolism of Umeclidinium can be decreased when combined with Acebutolol.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Umeclidinium bromide7AN603V4JV869113-09-7PEJHHXHHNGORMP-UHFFFAOYSA-M
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Incruse ElliptaPowder, metered55 mcgRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
Incruse ElliptaPowder62.5 mcg / actRespiratory (inhalation)Glaxosmithkline Inc2015-04-27Not applicableCanada flag
Incruse ElliptaPowder, metered55 mcgRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
Incruse ElliptaAerosol, powder62.5 ug/1OralGlaxosmithkline Inc2014-04-30Not applicableUS flag
Incruse ElliptaPowder, metered55 mcgRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
AnoroUmeclidinium bromide (55 micrograms) + Vilanterol trifenatate (22 micrograms)Powder, meteredRespiratory (inhalation)Glaxosmithkline Inc2016-09-08Not applicableEU flag
Anoro ElliptaUmeclidinium bromide (62.5 ug/1) + Vilanterol trifenatate (25 ug/1)PowderRespiratory (inhalation)Glaxosmithkline Inc2014-01-31Not applicableUS flag
ANORO ELLIPTAUmeclidinium (55 µg) + Vilanterol (22 µg)PowderRespiratory (inhalation)Glaxosmithkline Inc2014-10-03Not applicableItaly flag

Categories

ATC Codes
R03AL08 — Vilanterol, umeclidinium bromide and fluticasone furoateR03AL03 — Vilanterol and umeclidinium bromideR03BB07 — Umeclidinium bromide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Diphenylmethanes
Direct Parent
Diphenylmethanes
Alternative Parents
Benzylethers / Quinuclidines / Aralkylamines / Piperidines / Tetraalkylammonium salts / Tertiary alcohols / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Organic salts
show 3 more
Substituents
Alcohol / Amine / Aralkylamine / Aromatic alcohol / Aromatic heteropolycyclic compound / Azacycle / Benzylether / Dialkyl ether / Diphenylmethane / Ether
show 14 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
GE2T1418SV
CAS number
869185-19-3
InChI Key
FVTWTVQXNAJTQP-UHFFFAOYSA-N
InChI
InChI=1S/C29H34NO2/c31-29(26-12-6-2-7-13-26,27-14-8-3-9-15-27)28-16-19-30(20-17-28,21-18-28)22-23-32-24-25-10-4-1-5-11-25/h1-15,31H,16-24H2/q+1
IUPAC Name
1-[2-(benzyloxy)ethyl]-4-(hydroxydiphenylmethyl)-1-azabicyclo[2.2.2]octan-1-ium
SMILES
OC(C1=CC=CC=C1)(C1=CC=CC=C1)C12CC[N+](CCOCC3=CC=CC=C3)(CC1)CC2

References

General References
  1. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [Article]
  2. Decramer M, Maltais F, Feldman G, Brooks J, Harris S, Mehta R, Crater G: Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol. 2013 Jan 15;185(2):393-9. doi: 10.1016/j.resp.2012.08.022. Epub 2012 Sep 28. [Article]
  3. Tal-Singer R, Cahn A, Mehta R, Preece A, Crater G, Kelleher D, Pouliquen IJ: Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol. 2013 Feb 15;701(1-3):40-8. doi: 10.1016/j.ejphar.2012.12.019. Epub 2012 Dec 28. [Article]
  4. Scott LJ, Hair P: Umeclidinium/Vilanterol: first global approval. Drugs. 2014 Mar;74(3):389-95. doi: 10.1007/s40265-014-0186-8. [Article]
  5. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]
  6. Gosens R, Zaagsma J, Meurs H, Halayko AJ: Muscarinic receptor signaling in the pathophysiology of asthma and COPD. Respir Res. 2006 May 9;7(1):73. doi: 10.1186/1465-9921-7-73. [Article]
  7. FDA Approved Drug Products: INCRUSE ELLIPTA (umeclidinium inhalation powder) for oral inhalation use [Link]
  8. Health Canada Approved Drug Proucts: INCRUSE ELLIPTA (umeclidinium dry powder) for oral inhalation [Link]
  9. FDA Approved Drug Products: ANORO ELLIPTA (umeclidinium and vilanterol inhalation powder) for oral inhalation use [Link]
  10. FDA Approved Drug Products: Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) powder for inhalation (December 2022) [Link]
  11. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW: Umeclidinium Bromide [Link]
  12. Health Canada Approved Drug Proucts: ANORO ELLIPTA (umeclidinium/vilanterol powder) for oral inhalation [Link]
  13. Health Canada Approved Drug Proucts: TRELEGY ELLIPTA (fluticasone furoate/umeclidinium/vilanterol powder) for oral inhalation [Link]
  14. GSK receives approval for Incruse™ Ellipta® (umeclidinium) in the US for the treatment of COPD [Link]
  15. FDA approves Anoro Ellipta to treat chronic obstructive pulmonary disease [Link]
  16. FDA approves Trelegy Ellipta as the first once-daily single inhaler triple therapy for the treatment of both asthma and COPD in the US [Link]
  17. FDA Approved Drug Products: Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) powder for inhalation (June 2023) [Link]
  18. FDA Approved Drug Products: INCRUSE ELLIPTA (umeclidinium inhalation powder), for oral inhalation use (Jan 2024) [Link]
KEGG Drug
D10180
PubChem Compound
11519070
PubChem Substance
347827824
ChemSpider
9693858
BindingDB
50267614
RxNav
1487514
ChEBI
79041
ChEMBL
CHEMBL1187833
ZINC
ZINC000034608502
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Umeclidinium_bromide

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableChronic Obstructive Pulmonary Disease (COPD)4somestatusstop reasonjust information to hide
4CompletedBasic ScienceChronic Obstructive Pulmonary Disease (COPD)1somestatusstop reasonjust information to hide
4CompletedTreatmentChronic Obstructive Pulmonary Disease (COPD)4somestatusstop reasonjust information to hide
4Not Yet RecruitingPreventionChronic Obstructive Pulmonary Disease (COPD)1somestatusstop reasonjust information to hide
4RecruitingPreventionChronic Obstructive Pulmonary Disease (COPD)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
PowderBuccal
Aerosol, powderRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)62.5 mcg
PowderOral; Respiratory (inhalation)55 mcg
TabletOral62.5 mg
PowderBuccal74.200 mcg
Aerosol, powderOral62.5 ug/1
PowderRespiratory (inhalation)62.5 mcg / act
PowderRespiratory (inhalation)62.5 mcg/1blister
Powder, meteredRespiratory (inhalation)55 MCG
Aerosol, powderRespiratory (inhalation)62.5 mg
Powder, meteredRespiratory (inhalation)62.5 mcg
PowderRespiratory (inhalation)55 mcg
Aerosol, powderRespiratory (inhalation)55 mcg
PowderRespiratory (inhalation)
Powder, meteredRespiratory (inhalation)
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5873360Yes1999-02-232016-08-23US flag
US7101866No2006-09-052021-08-03US flag
US7439393Yes2008-10-212025-11-21US flag
US6759398No2004-07-062021-08-03US flag
USRE44874No2014-04-292023-03-23US flag
US6537983No2003-03-252021-08-03US flag
US8511304Yes2013-08-202027-12-14US flag
US7629335No2009-12-082021-08-03US flag
US8161968Yes2012-04-242028-08-05US flag
US8746242Yes2014-06-102031-04-11US flag
US8113199Yes2012-02-142028-04-23US flag
US7776895No2010-08-172022-09-11US flag
US8534281Yes2013-09-172030-09-08US flag
US6878698No2005-04-122021-08-03US flag
US8309572No2012-11-132025-04-27US flag
US8183257No2012-05-222025-07-27US flag
US7488827No2009-02-102025-04-27US flag
US7498440No2009-03-032025-04-27US flag
US8201556No2012-06-192029-02-05US flag
US9333310Yes2016-05-102028-04-02US flag
US9750726No2017-09-052030-11-29US flag
US9750762No2017-09-052030-11-29US flag
US11090294No2021-08-172030-11-29US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility1.94e-05 mg/mLALOGPS
logP2.88ALOGPS
logP0.68Chemaxon
logS-7.4ALOGPS
pKa (Strongest Acidic)13.04Chemaxon
pKa (Strongest Basic)-3.7Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area29.46 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity141.75 m3·mol-1Chemaxon
Polarizability50.42 Å3Chemaxon
Number of Rings5Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-000x-6696000000-9b62f23b3d6560b76225
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-191.803
predicted
DeepCCS 1.0 (2019)
[M+H]+194.19856
predicted
DeepCCS 1.0 (2019)
[M+Na]+200.1111
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover
Specific Function
acetylcholine binding
Gene Name
CHRM3
Uniprot ID
P20309
Uniprot Name
Muscarinic acetylcholine receptor M3
Molecular Weight
66127.445 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is adenylate cyclase inhibition. Signaling promotes phospholipase C activity, leading to the release of inositol trisphosphate (IP3); this then triggers calcium ion release into the cytosol
Specific Function
arrestin family protein binding
Gene Name
CHRM2
Uniprot ID
P08172
Uniprot Name
Muscarinic acetylcholine receptor M2
Molecular Weight
51714.605 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover
Specific Function
G protein-coupled acetylcholine receptor activity
Gene Name
CHRM1
Uniprot ID
P11229
Uniprot Name
Muscarinic acetylcholine receptor M1
Molecular Weight
51420.375 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase
Specific Function
G protein-coupled acetylcholine receptor activity
Gene Name
CHRM4
Uniprot ID
P08173
Uniprot Name
Muscarinic acetylcholine receptor M4
Molecular Weight
53048.65 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover
Specific Function
G protein-coupled acetylcholine receptor activity
Gene Name
CHRM5
Uniprot ID
P08912
Uniprot Name
Muscarinic acetylcholine receptor M5
Molecular Weight
60073.205 Da
References
  1. Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants
Specific Function
anandamide 11,12 epoxidase activity
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [Article]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
Specific Function
antioxidant activity
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Albumin
Molecular Weight
69365.94 Da
References
  1. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW: Umeclidinium Bromide [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Functions as a transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
Specific Function
Not Available
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23539.43 Da
References
  1. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW: Umeclidinium Bromide [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function
ABC-type xenobiotic transporter activity
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
ATP-dependent translocase ABCB1
Molecular Weight
141477.255 Da
References
  1. Feldman GJ, Edin A: The combination of umeclidinium bromide and vilanterol in the management of chronic obstructive pulmonary disease: current evidence and future prospects. Ther Adv Respir Dis. 2013 Dec;7(6):311-9. doi: 10.1177/1753465813499789. Epub 2013 Sep 3. [Article]
  2. FDA Approved Drug Products: INCRUSE ELLIPTA (umeclidinium inhalation powder) for oral inhalation use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Negligible at clinical doses
General Function
Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:11388889, PubMed:11408531, PubMed:12439218, PubMed:12719534, PubMed:15389554, PubMed:16263091, PubMed:16272756, PubMed:16581093, PubMed:19536068, PubMed:21128598, PubMed:23680637, PubMed:24961373, PubMed:34040533, PubMed:9187257, PubMed:9260930, PubMed:9655880). Functions as a pH- and Na(+)-independent, bidirectional transporter (By similarity). Cation cellular uptake or release is driven by the electrochemical potential (i.e. membrane potential and concentration gradient) and substrate selectivity (By similarity). Hydrophobicity is a major requirement for recognition in polyvalent substrates and inhibitors (By similarity). Primarily expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (By similarity). Most likely functions as an uptake carrier in enterocytes contributing to the intestinal elimination of organic cations from the systemic circulation (PubMed:16263091). Transports endogenous monoamines such as N-1-methylnicotinamide (NMN), guanidine, histamine, neurotransmitters dopamine, serotonin and adrenaline (PubMed:12439218, PubMed:24961373, PubMed:35469921, PubMed:9260930). Also transports natural polyamines such as spermidine, agmatine and putrescine at low affinity, but relatively high turnover (PubMed:21128598). Involved in the hepatic uptake of vitamin B1/thiamine, hence regulating hepatic lipid and energy metabolism (PubMed:24961373). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Transports dopaminergic neuromodulators cyclo(his-pro) and salsolinol with lower efficency (PubMed:17460754). Also capable of transporting non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). May contribute to the transport of cationic compounds in testes across the blood-testis-barrier (Probable). Also involved in the uptake of xenobiotics tributylmethylammonium (TBuMA), quinidine, N-methyl-quinine (NMQ), N-methyl-quinidine (NMQD) N-(4,4-azo-n-pentyl)-quinuclidine (APQ), azidoprocainamide methoiodide (AMP), N-(4,4-azo-n-pentyl)-21-deoxyajmalinium (APDA) and 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:11408531, PubMed:15389554, PubMed:35469921, PubMed:9260930)
Specific Function
(R)-carnitine transmembrane transporter activity
Gene Name
SLC22A1
Uniprot ID
O15245
Uniprot Name
Solute carrier family 22 member 1
Molecular Weight
61153.345 Da
References
  1. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW: Umeclidinium Bromide [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Curator comments
Negligible at clinical doses
General Function
Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
Specific Function
acetylcholine transmembrane transporter activity
Gene Name
SLC22A2
Uniprot ID
O15244
Uniprot Name
Solute carrier family 22 member 2
Molecular Weight
62579.99 Da
References
  1. CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW: Umeclidinium Bromide [Link]

Drug created at May 19, 2015 16:00 / Updated at November 03, 2024 19:35