Details of the Drug Combination

General Information of Drug Combination (ID: DC0VE6B)

• Drug Combination Name: Levonorgestrel + Ulipristal
• Indication: Contraception; Status: Phase 4 [1]
• Component Drugs:
  Levonorgestrel (DM1DP7T): Small molecular drug
  Ulipristal (DMBNI20): 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	[6]

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	[7]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[8]
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B)	OTQ4W7MT	TR11B_HUMAN	Increases Expression	[9]
Tumor necrosis factor ligand superfamily member 11 (TNFSF11)	OTJEPKEQ	TNF11_HUMAN	Decreases Expression	[9]
Low-density lipoprotein receptor (LDLR)	OTH559LU	LDLR_HUMAN	Affects Expression	[10]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Decreases Secretion	[11]
Sex hormone-binding globulin (SHBG)	OTPWU5IW	SHBG_HUMAN	Affects Binding	[12]
Prostate-specific antigen (KLK3)	OTFGSBFJ	KLK3_HUMAN	Increases Expression	[13]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[14]
Proliferation marker protein Ki-67 (MKI67)	OTA8N1QI	KI67_HUMAN	Decreases Expression	[14]

Indication(s) of Ulipristal

Disease Entry	ICD 11	Status	REF
Contraception	QA21	Approved	[4]

Ulipristal Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Progesterone receptor (PGR)	TTUV8G9	PRGR_HUMAN	Modulator	[4]

Ulipristal Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[15]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[16]

References

• [1] ClinicalTrials.gov (NCT02577601) Impact of Combined Hormonal Contraceptives on UPA
• [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] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3. Chem Biol Interact. 2011 May 30;191(1-3):227-33.
• [9] [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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Emergency contraception. Gynecol Endocrinol. 2013 Mar;29 Suppl 1:1-14.
• [16] The clinical pharmacology and pharmacokinetics of ulipristal acetate for the treatment of uterine fibroids. Reprod Sci. 2015 Apr;22(4):476-83.