Details of the Drug Combination

General Information of Drug Combination (ID: DCEU4AK)

• Drug Combination Name: Levonorgestrel + Efavirenz
• Indication: HIV; Status: Phase 1 [1]
• Component Drugs:
  Levonorgestrel (DM1DP7T): Small molecular drug
  Efavirenz (DMC0GSJ): 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 Efavirenz

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[4]

Efavirenz Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[15]

Efavirenz Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[17]

Efavirenz Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[19]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[20]

Efavirenz Interacts with 32 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[21]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[22]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[22]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[23]
Dynamin-1-like protein (DNM1L)	OTXK1Q1G	DNM1L_HUMAN	Affects Localization	[24]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[25]
Dynamin-like 120 kDa protein, mitochondrial (OPA1)	OTJGNWPW	OPA1_HUMAN	Increases Expression	[24]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Increases Expression	[24]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Expression	[26]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[27]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Secretion	[28]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[28]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[25]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Decreases Expression	[28]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Increases Expression	[26]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[28]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[28]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Increases Secretion	[28]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Increases Expression	[26]
Calnexin (CANX)	OTYP1F6J	CALX_HUMAN	Affects Localization	[24]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[24]
Lon protease homolog, mitochondrial (LONP1)	OT665WYT	LONM_HUMAN	Increases Expression	[24]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Decreases Expression	[28]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[28]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[28]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[25]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[28]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[28]
Regulator of microtubule dynamics protein 3 (RMDN3)	OTKO7AUM	RMD3_HUMAN	Increases Expression	[24]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[25]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[24]
Mitochondrial fission 1 protein (FIS1)	OT2HL10J	FIS1_HUMAN	Increases Expression	[24]

References

• [1] ClinicalTrials.gov (NCT01789879) A Pharmacokinetic Evaluation of Levonorgestrel Implant and Antiretroviral Therapy
• [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] Approved antiretroviral drugs. Antiretroviral Drugs. Company report of AVERT. 2009.
• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [16] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [17] Induction of multiple drug transporters by efavirenz. J Pharmacol Sci. 2009 Feb;109(2):242-50.
• [18] Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol. 2004 Nov;44(11):1273-81.
• [19] CYP2B6 genotype-dependent inhibition of CYP1A2 and induction of CYP2A6 by the antiretroviral drug efavirenz in healthy volunteers. Clin Transl Sci. 2019 Nov;12(6):657-666.
• [20] Evaluation of CYP2B6 induction and prediction of clinical drug-drug interactions: considerations from the IQ consortium induction working group-an industry perspective. Drug Metab Dispos. 2016 Oct;44(10):1720-30.
• [21] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [22] Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol. 2001 Jan;41(1):85-91.
• [23] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [24] Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress. Br J Pharmacol. 2017 Dec;174(23):4409-4429. doi: 10.1111/bph.14045. Epub 2017 Nov 7.
• [25] Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicol Appl Pharmacol. 2011 Dec 1;257(2):227-34. doi: 10.1016/j.taap.2011.09.008. Epub 2011 Sep 19.
• [26] Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab. 2005 Oct;90(10):5663-71. doi: 10.1210/jc.2005-0367. Epub 2005 Jul 19.
• [27] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [28] Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res. 2011 Aug;91(2):112-9. doi: 10.1016/j.antiviral.2011.04.018. Epub 2011 May 17.