Details of the Drug Combination

General Information of Drug Combination (ID: DCKO6BT)

• Drug Combination Name: Loratadine + Montelukast
• Indication: Allergic rhinitis; Status: Phase 1 [1]
• Component Drugs:
  Loratadine (DMF3AN7): Small molecular drug
  Montelukast (DMD157S): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Loratadine

Disease Entry	ICD 11	Status	REF
Allergy	4A80-4A85	Approved	[2]
Common cold	CA00	Approved	[3]
Seasonal allergic rhinitis	CA08.01	Approved	[3]
Vasomotor/allergic rhinitis	CA08	Approved	[3]
Allergic rhinitis	CA08.0	Discontinued in Phase 2	[4]

Loratadine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[8]

Loratadine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Loratadine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[12]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[15]

Loratadine Interacts with 27 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[16]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[17]
Histamine H1 receptor (HRH1)	OT8F9FV6	HRH1_HUMAN	Affects Binding	[16]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[18]
Alpha-1-antichymotrypsin (SERPINA3)	OT9BP2S0	AACT_HUMAN	Increases Expression	[18]
Serine protease hepsin (HPN)	OT7QNA61	HEPS_HUMAN	Increases Expression	[18]
Fatty acid-binding protein, liver (FABP1)	OTR34ETM	FABPL_HUMAN	Increases Expression	[18]
Asparagine synthetase (ASNS)	OT8R922G	ASNS_HUMAN	Increases Expression	[18]
Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3)	OT2HZK5M	GTR3_HUMAN	Decreases Expression	[18]
Lanosterol synthase (LSS)	OT9W2SFH	LSS_HUMAN	Increases Expression	[18]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[18]
Transgelin (TAGLN)	OTAEZ0KP	TAGL_HUMAN	Decreases Expression	[18]
Nuclear receptor subfamily 0 group B member 2 (NR0B2)	OT7UVICX	NR0B2_HUMAN	Increases Expression	[18]
Lysophospholipase D GDPD3 (GDPD3)	OTOHM9QM	GDPD3_HUMAN	Increases Expression	[18]
Polyunsaturated fatty acid 5-lipoxygenase (ALOX5)	OT7FOIK2	LOX5_HUMAN	Decreases Activity	[16]
AP-1 complex subunit sigma-1A (AP1S1)	OTQ2H8DN	AP1S1_HUMAN	Decreases Expression	[19]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[20]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[21]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[22]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[23]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[24]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Cleavage	[23]
Small ribosomal subunit protein eS6 (RPS6)	OTT4D1LN	RS6_HUMAN	Decreases Expression	[23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[25]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Cleavage	[23]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Affects Binding	[26]
Multidrug resistance-associated protein 1 (ABCC1)	OTGUN89S	MRP1_HUMAN	Decreases Response To Substance	[27]

Indication(s) of Montelukast

Disease Entry	ICD 11	Status	REF
Allergic asthma	CA23.0	Approved	[5]
Allergic rhinitis	CA08.0	Approved	[5]
Asthma	CA23	Approved	[6]
Intrinsic asthma	N.A.	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2/3	[7]

Montelukast Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN cysteinyl leukotriene receptor (CysLTR)	TTSB6CA	CLTR1_HUMAN; CLTR2_HUMAN	Antagonist	[28]
Leukotriene CysLT1 receptor (CYSLTR1)	TTGKOY9	CLTR1_HUMAN	Antagonist	[29]

Montelukast Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[30]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[31]

Montelukast Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[32]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[32]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[33]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[34]

References

• [1] Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics. 2001 Sep;108(3):E48.
• [2] 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: 7216).
• [3] Loratadine FDA Label
• [4] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800015252)
• [5] Montelukast FDA Label
• [6] 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: 3340).
• [7] The COvid-19 Symptom MOntelukast Trial (COSMO)
• [8] Clinical research of Ibudilast on treating the steroid resistant allergic rhinitis. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009 Jan;23(2):63-6.
• [9] P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists. Drug Metab Dispos. 2003 Mar;31(3):312-8.
• [10] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [11] Metabolism of loratadine and further characterization of its in vitro metabolites. Drug Metab Lett. 2009 Aug;3(3):162-70.
• [12] In vitro characterization of the inhibition profile of loratadine, desloratadine, and 3-OH-desloratadine for five human cytochrome P-450 enzymes. Drug Metab Dispos. 2001 Sep;29(9):1173-5.
• [13] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [14] In vitro inhibition of human liver drug metabolizing enzymes by second generation antihistamines. Chem Biol Interact. 1999 Nov 15;123(1):63-79.
• [15] Advances in high-resolution MS and hepatocyte models solve a long-standing metabolism challenge: the loratadine story. Bioanalysis. 2016 Aug;8(16):1645-62.
• [16] Cetirizine and loratadine-based antihistamines with 5-lipoxygenase inhibitory activity. Bioorg Med Chem Lett. 2004 Nov 15;14(22):5591-4.
• [17] Examination of 209 drugs for inhibition of cytochrome P450 2C8. J Clin Pharmacol. 2005 Jan;45(1):68-78.
• [18] A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005 Feb;83(2):282-92.
• [19] In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol Sci. 2007 Sep;99(1):162-73.
• [20] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [21] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [22] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [23] H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells. Exp Hematol. 2010 Oct;38(10):896-907. doi: 10.1016/j.exphem.2010.05.008. Epub 2010 Jun 1.
• [24] Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease. Toxicol Sci. 2012 Oct;129(2):346-62. doi: 10.1093/toxsci/kfs208. Epub 2012 Jun 14.
• [25] Loratadine blockade of K(+) channels in human heart: comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther. 2000 Jan;292(1):261-4.
• [26] Testing of the inhibitory effects of loratadine and desloratadine on SARS-CoV-2 spike pseudotyped virus viropexis. Chem Biol Interact. 2021 Apr 1;338:109420. doi: 10.1016/j.cbi.2021.109420. Epub 2021 Feb 18.
• [27] Mrp2 is involved in the efflux and disposition of fosinopril. J Appl Toxicol. 2013 Jun;33(6):458-65. doi: 10.1002/jat.1767. Epub 2011 Nov 17.
• [28] As a potential treatment of COVID-19: Montelukast. Med Hypotheses. 2020 May 11;142:109828.
• [29] Protective potential of montelukast against hepatic ischemia/reperfusion injury in rats. J Surg Res. 2010 Mar;159(1):588-94.
• [30] Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. J Clin Pharmacol. 2011 May;51(5):751-60.
• [31] Effects of polymorphisms of the SLCO2B1 transporter gene on the pharmacokinetics of montelukast in humans. J Clin Pharmacol. 2013 Nov;53(11):1186-93.
• [32] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [33] Determinants of cytochrome P450 2C8 substrate binding: structures of complexes with montelukast, troglitazone, felodipine, and 9-cis-retinoic acid. J Biol Chem. 2008 Jun 20;283(25):17227-37.
• [34] In vitro metabolism of montelukast by cytochrome P450s and UDP-glucuronosyltransferases. Drug Metab Dispos. 2015 Dec;43(12):1905-16.