Details of the Drug Combination

General Information of Drug Combination (ID: DC1ES9G)

• Drug Combination Name: Levonorgestrel + Meloxicam
• Indication: Pregnancy Prevention; Status: Phase 2 [1]
• Component Drugs:
  Levonorgestrel (DM1DP7T): Small molecular drug
  Meloxicam (DM2AR7L): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Levonorgestrel

Disease Entry	ICD 11	Status	REF
Atypical endometrial hyperplasia	N.A.	Approved	[2]
Contraception	QA21	Approved	[3]
Hot flushes	GA30	Approved	[2]
Menorrhagia	GA20.50	Approved	[2]

Levonorgestrel Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Progesterone receptor (PGR)	TTUV8G9	PRGR_HUMAN	Binder	[7]

Levonorgestrel Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[8]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[9]
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B)	OTQ4W7MT	TR11B_HUMAN	Increases Expression	[10]
Tumor necrosis factor ligand superfamily member 11 (TNFSF11)	OTJEPKEQ	TNF11_HUMAN	Decreases Expression	[10]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Affects Expression	[11]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[12]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Affects Binding	[13]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[14]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[15]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[15]

Indication(s) of Meloxicam

Disease Entry	ICD 11	Status	REF
Arthritis	FA20	Approved	[4]
Osteoarthritis	FA00-FA05	Approved	[5]

Meloxicam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (COX-2)	TTVKILB	PGH2_HUMAN	Inhibitor	[16]

Meloxicam Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[18]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]

Meloxicam Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Activity	[20]
Proliferating cell nuclear antigen (PCNA)	OTHZ1RIA	PCNA_HUMAN	Decreases Expression	[21]
L-selectin (SELL)	OT6RAJZR	LYAM1_HUMAN	Affects Expression	[22]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[21]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[23]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[21]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Decreases Activity	[24]
ATP-binding cassette sub-family C member 4 (ABCC4)	OTO27PAL	MRP4_HUMAN	Affects Binding	[25]

References

• [1] ClinicalTrials.gov (NCT05695352) Oral Levonorgestrel Plus Meloxicam, IG-002 Delays Ovulation in Normal Menstruating Women by Seven Days
• [2] Levonorgestrel FDA Label
• [3] 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: 2881).
• [4] 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: 7220).
• [5] Meloxicam FDA Label
• [6] Effects of 17beta-estradiol, progesterone, synthetic progestins, tibolone, and raloxifene on vascular endothelial growth factor and Thrombospondin-1 messenger RNA in breast cancer cells. Int J Gynecol Cancer. 2006;16 Suppl 2:560-3. doi: 10.1111/j.1525-1438.2006.00696.x.
• [7] Met909 plays a key role in the activation of the progesterone receptor and also in the high potency of 13-ethyl progestins. Mol Pharmacol. 2009 Jun;75(6):1317-24.
• [8] P-glycoprotein (P-gp/MDR1)-mediated efflux of sex-steroid hormones and modulation of P-gp expression in vitro. Pharm Res. 2004 Jul;21(7):1284-93.
• [9] Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3. Chem Biol Interact. 2011 May 30;191(1-3):227-33.
• [10] [Effect of nylestriol and levonorgestrel on the expression of Opg/OPGL in human osteosarcoma MG-63 cell lines]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2004 Dec;29(6):667-70.
• [11] Study of low-density lipoprotein receptor regulation by oral (steroid) contraceptives: desogestrel, levonorgestrel and ethinyl estradiol in JEG-3 cell line and placental tissue. Contraception. 2007 Oct;76(4):297-305. doi: 10.1016/j.contraception.2007.06.011. Epub 2007 Sep 14.
• [12] Relative progestational and androgenic activity of four progestins used for male hormonal contraception assessed in vitro in relation to their ability to suppress LH secretion in the castrate male rat. Mol Cell Endocrinol. 2010 Oct 26;328(1-2):16-21. doi: 10.1016/j.mce.2010.06.010. Epub 2010 Jun 25.
• [13] Serum distribution of the major metabolites of norgestimate in relation to its pharmacological properties. Contraception. 2003 Feb;67(2):93-9. doi: 10.1016/s0010-7824(02)00473-0.
• [14] Effects of natural products and nutraceuticals on steroid hormone-regulated gene expression. Clin Chim Acta. 2001 Oct;312(1-2):213-9. doi: 10.1016/s0009-8981(01)00626-x.
• [15] Effect of menstrual cycle and hormonal treatment on ki-67 and bcl-2 expression and adenomyosis. Gynecol Endocrinol. 2005 Mar;20(3):127-31. doi: 10.1080/09513590400021086.
• [16] Meloxicam: selective COX-2 inhibition in clinical practice. Semin Arthritis Rheum. 1997 Jun;26(6 Suppl 1):21-7.
• [17] Activation of human cytochrome P-450 3A4-catalyzed meloxicam 5'-methylhydroxylation by quinidine and hydroquinidine in vitro. J Pharmacol Exp Ther. 1999 Jul;290(1):1-8.
• [18] Genetically based impairment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):607-20.
• [19] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [20] Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat. 2007 Jan;82(1-4):85-94.
• [21] Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice. Cancer Sci. 2009 Nov;100(11):2226-33. doi: 10.1111/j.1349-7006.2009.01306.x. Epub 2009 Aug 4.
• [22] Structure-function relationship and role of tumor necrosis factor-alpha-converting enzyme in the down-regulation of L-selectin by non-steroidal anti-inflammatory drugs. J Biol Chem. 2002 Oct 11;277(41):38212-21. doi: 10.1074/jbc.M205142200. Epub 2002 Jul 29.
• [23] Inhibiting AKT signaling pathway with cilostazol and meloxicam synergism for suppressing K562 cells in vitro. J Biochem Mol Toxicol. 2022 Nov;36(11):e23185. doi: 10.1002/jbt.23185. Epub 2022 Aug 3.
• [24] Regulatory effects of non-steroidal anti-inflammatory drugs on cardiac ion channels Nav1.5 and Kv11.1. Chem Biol Interact. 2021 Apr 1;338:109425. doi: 10.1016/j.cbi.2021.109425. Epub 2021 Feb 19.
• [25] Multichannel liquid chromatography-tandem mass spectrometry cocktail method for comprehensive substrate characterization of multidrug resistance-associated protein 4 transporter. Pharm Res. 2007 Dec;24(12):2281-96.