Details of the Drug-Related molecule(s) Interaction Atlas

General Information of Drug (ID: DMFDC0Q)

• Drug Name: Tiotropium Drug Info
• Synonyms: 186691-13-4; UNII-0EB439235F; 0EB439235F; [3H]tiotropium; (1r,2r,4s,5s,7s)-7-{[hydroxy(Dithiophen-2-Yl)acetyl]oxy}-9,9-Dimethyl-3-Oxa-9-Azoniatricyclo[3310~2,4~]nonane; NCGC00167971-01; 0HK; (1R,2R,4S,5S)-7-{[2-hydroxy-2,2-bis(thiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azatricyclo[3310^{2,4}]nonan-9-ium; GTPL367; SCHEMBL4662461; GTPL8592; DTXSID5044281; CHEMBL3305968; Spiriva (TN); Tiotropium bromide [USAN:INN]; (1A,2A,4A,5A,7A)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatri-cyclo[331024]nonane bromide; (1a,2,4,5a,7)-7-[(2-Hydroxy-2,2-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[33102,4]nonane bromide; 7-{[hydroxy(dithiophen-2-yl)acetyl]oxy}-9,9-dimethyl-3-oxa-9-azoniatricyclo[33102,4]nonane bromide

Indication

Disease Entry	ICD 11	Status	REF
Chronic obstructive pulmonary disease	CA22	Approved	[1]
Pulmonary emphysema	CA21.Z	Approved	[2]
Asthma	CA23	Investigative	[2]

• Therapeutic Class: Bronchodilator Agents
• Cross-matching ID:
  PubChem CID: 5487427
  ChEBI ID: CHEBI:90960
  CAS Number: CAS 186691-13-4
  TTD Drug ID: DMFDC0Q
  VARIDT Drug ID: DR00017
  ACDINA Drug ID: D00681

Molecule-Related Drug Atlas

Drug(s) Targeting Muscarinic acetylcholine receptor (CHRM)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetylcholine	DMDF79Z	Cataract	9B10	Approved	[7]
Darifenacin	DMWXLYZ	Overactive bladder	GC50.0	Approved	[8]
Methylscopolamine	DM5VWOB	Peptic ulcer	DA61	Approved	[9]
Clidinium	DMUMQZ0	Abdominal stomach pain	DD91.4	Approved	[10]
Oxybutynin hydrochloride	DMF2KLU	Urinary incontinence	MF50.2	Approved	[11]
Incruse Ellipta	DM32GSJ	Chronic obstructive pulmonary disease	CA22	Approved	[12]
Revefenacin	DMMP5SI	Chronic obstructive pulmonary disease	CA22	Approved	[13]
Scopolamine	DMOM8AL	Addictive disorder	6C50-6C5Z	Approved	[14]
Isopropamide iodide	DMQYV60	Allergic rhinitis	CA08.0	Approved	[15]
SUN-101	DMXNZQK	Chronic obstructive pulmonary disease	CA22	Phase 3	[16]

Drug(s) Targeting Muscarinic acetylcholine receptor M3 (CHRM3)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tolterodine	DMSHPW8	Overactive bladder	GC50.0	Approved	[17]
ACECLIDINE	DMOLNCZ	Glaucoma/ocular hypertension	9C61	Approved	[18]
Ipratropium	DMFQ320	Obstructive lung disease	CA22.Z	Approved	[19]
Darifenacin	DMWXLYZ	Overactive bladder	GC50.0	Approved	[20]
Methacholine Chloride	DMGS4QH	Asthma	CA23	Approved	[21]
SMT-D002	DM1I93C	Seborrhea	ED91.2	Approved	[22]
Solifenacin	DMG592Q	Overactive bladder	GC50.0	Approved	[23]
Methylscopolamine	DM5VWOB	Peptic ulcer	DA61	Approved	[24]
Cevimeline	DMWSMND	Sjogren syndrome	4A43.20	Approved	[25]
Methscopolamine Bromide	DMHP8FI	Nausea and vomiting	MD90	Approved	[26]

Drug(s) Transported By Organic cation transporter 1 (SLC22A1)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dinoprostone	DMTYOPD	Medical abortion	JA00.1Z	Approved	[27]
Cisplatin	DMRHGI9	Adenocarcinoma	2D40	Approved	[28]
Imatinib	DM7RJXL	Acute lymphoblastic leukaemia	2A85	Approved	[29]
Oxaliplatin	DMQNWRD	Adenocarcinoma	2D40	Approved	[30]
Zidovudine	DM4KI7O	Human immunodeficiency virus infection	1C62	Approved	[31]
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[32]
Sorafenib	DMS8IFC	Adenocarcinoma	2D40	Approved	[33]
Quinine	DMSWYF5	Malaria	1F40-1F45	Approved	[34]
Dopamine	DMPGUCF	Acromegaly	5A60.0	Approved	[35]
Propranolol	DM79NTF	Angina pectoris	BA40	Approved	[36]

Drug(s) Transported By Organic cation/carnitine transporter 2 (SLC22A5)

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Verapamil	DMA7PEW	Angina pectoris	BA40	Approved	[37]
Quinine	DMSWYF5	Malaria	1F40-1F45	Approved	[38]
Entecavir	DM7VTQO	Hepatitis B virus infection	1E51.0	Approved	[39]
Levacecarnine hci	DMJBOCR	Cognitive impairment	6D71	Approved	[40]
Amphetamine	DMSZQAK	Attention deficit hyperactivity disorder	6A05.Z	Approved	[41]
Potassium Chloride	DMMTAJC	Hypokalemia	5C77	Approved	[42]
Ipratropium	DMFQ320	Obstructive lung disease	CA22.Z	Approved	[5]
Mepyramine	DMB4SFH	Allergic rhinitis	CA08.0	Approved	[43]
Acetylcarnitine	DM4UE3K	Chronic fatigue syndrome	8E49	Phase 4	[44]
acetyl-L-carnitine	DM74HGJ	Discovery agent	N.A.	Investigative	[38]

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Muscarinic acetylcholine receptor (CHRM)	TTOXS3C	NOUNIPROTAC	Antagonist	[3]
Muscarinic acetylcholine receptor M3 (CHRM3)	TTQ13Z5	ACM3_HUMAN	Antagonist	[4]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[5]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[6]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 367).
• [2] Tiotropium FDA Label
• [3] 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.
• [4] DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6.
• [5] Transport of ipratropium, an anti-chronic obstructive pulmonary disease drug, is mediated by organic cation/carnitine transporters in human bronchial epithelial cells: implications for carrier-mediated pulmonary absorption. Mol Pharm. 2010 Feb 1;7(1):187-95.
• [6] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [7] Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol Pharmacol. 2004 Jan;65(1):257-66.
• [8] Characterisation of [3H]-darifenacin as a novel radioligand for the study of muscarinic M3 receptors. J Recept Signal Transduct Res. 1997 Jan-May;17(1-3):177-84.
• [9] Lithocholylcholine, a bile acid/acetylcholine hybrid, is a muscarinic receptor antagonist. J Pharmacol Exp Ther. 2002 Oct;303(1):29-35.
• [10] Pharmacological comparison of the cloned human and rat M2 muscarinic receptor genes expressed in the murine fibroblast (B82) cell line. J Pharmacol Exp Ther. 1998 Feb;284(2):500-7.
• [11] Effects of propiverine hydrochloride (propiverine) on the muscarinic receptor binding affinity in guinea pig tissues and on salivation in conscious dogs. Nihon Yakurigaku Zasshi. 1999 Mar;113(3):157-66.
• [12] Clinical pipeline report, company report or official report of GlaxoSmithKline.
• [13] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [14] The amygdala modulates morphine-induced state-dependent memory retrieval via muscarinic acetylcholine receptors. Neuroscience. 2009 May 5;160(2):255-63.
• [15] Competitive and non-competitive antagonism exhibited by 'selective' antagonists at atrial and ileal muscarinic receptor subtypes. Br J Pharmacol. 1987 Apr;90(4):701-7.
• [16] Long-acting bronchodilators in COPD: Where are we now and where are we going Breathe 06/2014; 10(2):110-120.
• [17] Signal transduction underlying carbachol-induced contraction of human urinary bladder. J Pharmacol Exp Ther. 2004 Jun;309(3):1148-53.
• [18] Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists. J Med Chem. 1993 Apr 2;36(7):842-7.
• [19] Role of parasympathetic nerves and muscarinic receptors in allergy and asthma.Chem Immunol Allergy.2012;98:48-69.
• [20] M(1) and M(3) muscarinic receptors are involved in the release of urinary bladder-derived relaxant factor. Pharmacol Res. 2009 May;59(5):300-5.
• [21] Muscarinic M3-receptors mediate cholinergic synergism of mitogenesis in airway smooth muscle. Am J Respir Cell Mol Biol. 2003 Feb;28(2):257-62.
• [22] Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder. J Urol. 2004 Nov;172(5 Pt 1):2059-64.
• [23] Comparison of muscarinic receptor selectivity of solifenacin and oxybutynin in the bladder and submandibular gland of muscarinic receptor knockout ... Eur J Pharmacol. 2009 Aug 1;615(1-3):201-6.
• [24] Interaction of neuromuscular blocking drugs with recombinant human m1-m5 muscarinic receptors expressed in Chinese hamster ovary cells. Br J Pharmacol. 1998 Nov;125(5):1088-94.
• [25] Degradation of submandibular gland AQP5 by parasympathetic denervation of chorda tympani and its recovery by cevimeline, an M3 muscarinic receptor ... Am J Physiol Gastrointest Liver Physiol. 2008 Jul;295(1):G112-G123.
• [26] Agonist-regulated alteration of the affinity of pancreatic muscarinic cholinergic receptors. J Biol Chem. 1993 Oct 25;268(30):22436-43.
• [27] Are organic cation transporters capable of transporting prostaglandins? Naunyn Schmiedebergs Arch Pharmacol. 2005 Aug;372(2):125-30.
• [28] Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family). J Pharmacol Exp Ther. 2006 Nov;319(2):879-86.
• [29] Pharmacologic markers and predictors of responses to imatinib therapy in patients with chronic myeloid leukemia. Leuk Lymphoma. 2008 Apr;49(4):639-42.
• [30] Organic cation transporters are determinants of oxaliplatin cytotoxicity. Cancer Res. 2006 Sep 1;66(17):8847-57.
• [31] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [32] Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett. 2006 Mar 8;234(1):4-33.
• [33] Upregulation of histone acetylation reverses organic anion transporter 2 repression and enhances 5-fluorouracil sensitivity in hepatocellular carcinoma
• [34] Comparison of type I and type II organic cation transport by organic cation transporters and organic anion-transporting polypeptides. J Pharmacol Exp Ther. 2001 Jul;298(1):110-5.
• [35] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [36] Influx Transport of Cationic Drug at the Blood-Retinal Barrier: Impact on the Retinal Delivery of Neuroprotectants. Biol Pharm Bull. 2017;40(8):1139-1145.
• [37] Genetic variations of the SLC22A5 gene in the Chinese and Indian populations of Singapore. Drug Metab Pharmacokinet. 2010;25(1):112-9.
• [38] Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther. 1999 Nov;291(2):778-84.
• [39] Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir. Drug Metab Dispos. 2017 Mar;45(3):269-278.
• [40] Colistin is substrate of the carnitine/organic cation transporter 2 (OCTN2, SLC22A5). Drug Metab Dispos. 2017 Dec;45(12):1240-1244.
• [41] Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells. J Pharmacol Exp Ther. 2005 Jan;312(1):192-8.
• [42] Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Arch. 2010 Jul;460(2):505-23.
• [43] Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice. Biopharm Drug Dispos. 2009 Dec;30(9):495-507.
• [44] Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2. Arch Biochem Biophys. 2006 Aug 1;452(1):29-37.