Details of the Drug Combination

General Information of Drug Combination (ID: DCQ001S)

• Drug Combination Name: Entecavir + Lamivudine
• Indication: Hepatitis B virus infection; Status: Investigative [1]
• Component Drugs:
  Entecavir (DM7VTQO): Small molecular drug
  Lamivudine (DMI347A): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Entecavir

Disease Entry	ICD 11	Status	REF
Hepatitis B virus infection	1E51.0	Approved	[2]

Entecavir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Hepatitis B virus Reverse transcriptase (HBV RT)	TTS5K1M	DPOL_HBVA3	Modulator	[5]

Entecavir Interacts with 9 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[6]
Organic anion transporter 2 (SLC22A7)	DT0OC1Q	S22A7_HUMAN	Substrate	[7]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[6]
Peptide transporter 2 (SLC15A2)	DT8QKNP	S15A2_HUMAN	Substrate	[8]
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[6]
Concentrative nucleoside transporter 2 (SLC28A2)	DT82KPY	S28A2_HUMAN	Substrate	[6]
Concentrative Na(+)-nucleoside cotransporter 3 (SLC28A3)	DT4YL5R	S28A3_HUMAN	Substrate	[6]
Equilibrative nucleoside transporter 1 (SLC29A1)	DTXD1TQ	S29A1_HUMAN	Substrate	[6]
Equilibrative nucleoside transporter 2 (SLC29A2)	DTW78DQ	S29A2_HUMAN	Substrate	[6]

Indication(s) of Lamivudine

Disease Entry	ICD 11	Status	REF
Chronic HBV infection	1E51.0Z	Approved	[2]
Chronic hepatitis B virus infection	N.A.	Approved	[3]
Human immunodeficiency virus infection	1C62	Approved	[2]
Human immunodeficiency virus-1 infection	1C62	Approved	[4]
Diarrhea	ME05.1	Investigative	[3]

Lamivudine 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	[9]

Lamivudine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[11]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[12]

Lamivudine Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Deoxy-5'-nucleotidase 1 (NT5C)	DE4E31Z	NT5C_HUMAN	Metabolism	[13]
Phosphorylcholine transferase A (PCYT1A)	DEQYXD4	PCY1A_HUMAN	Metabolism	[14]
Phosphorylethanolamine transferase (PCYT2)	DEIX1PO	PCY2_HUMAN	Metabolism	[14]

Lamivudine Interacts with 19 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Uptake	[15]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Increases Uptake	[15]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[16]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[17]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[18]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[18]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[19]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[20]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[21]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[18]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Increases Secretion	[16]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[17]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Phosphorylation	[16]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[17]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[22]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[17]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[17]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[20]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[15]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Non-Hodgkin Lymphoma	DCBH8D1	N. A.	Phase 2	[23]
Hepatitis B Virus	DCNLS75	N. A.	Phase 1	[24]

References

• [1] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [2] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [3] Lamivudine FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Effect of hepatitis B virus reverse transcriptase variations on entecavir treatment response. J Infect Dis. 2014 Sep 1;210(5):701-7.
• [6] Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir. Drug Metab Dispos. 2017 Mar;45(3):269-278.
• [7] Human organic anion transporter 2 is an entecavir, but not tenofovir, transporter. Drug Metab Pharmacokinet. 2017 Feb;32(1):116-119.
• [8] The oligopeptide transporter 2-mediated reabsorption of entecavir in rat kidney. Eur J Pharm Sci. 2014 Feb 14;52:41-7.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Br J Clin Pharmacol. 2007 Nov;64(5):645-54.
• [11] Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos. 2012 Apr;33(3):170-8.
• [12] Relevance of the organic cation transporters 1 and 2 for antiretroviral drug therapy in human immunodeficiency virus infection. Drug Metab Dispos. 2008 Aug;36(8):1616-23.
• [13] Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010 Jan;85(1):39-58.
• [14] Model for intracellular Lamivudine metabolism in peripheral blood mononuclear cells ex vivo and in human immunodeficiency virus type 1-infected adolescents. Antimicrob Agents Chemother. 2006 Aug;50(8):2686-94.
• [15] Transport of lamivudine [(-)-beta-L-2',3'-dideoxy-3'-thiacytidine] and high-affinity interaction of nucleoside reverse transcriptase inhibitors with human organic cation transporters 1, 2, and 3. J Pharmacol Exp Ther. 2009 Apr;329(1):252-61. doi: 10.1124/jpet.108.146225. Epub 2009 Jan 13.
• [16] Nucleoside reverse transcriptase inhibitors induce a mitophagy-associated endothelial cytotoxicity that is reversed by coenzyme Q10 cotreatment. Toxicol Sci. 2013 Aug;134(2):323-34. doi: 10.1093/toxsci/kft105. Epub 2013 May 2.
• [17] Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells. Mutagenesis. 2005 Mar;20(2):139-46. doi: 10.1093/mutage/gei019. Epub 2005 Mar 22.
• [18] Effect of lamivudine treatment on plasma levels of transforming growth factor beta1, tissue inhibitor of metalloproteinases-1 and metalloproteinase-1 in patients with chronic hepatitis B. World J Gastroenterol. 2004 Sep 15;10(18):2661-5. doi: 10.3748/wjg.v10.i18.2661.
• [19] Lamivudine plus interleukin-12 combination therapy in chronic hepatitis B: antiviral and immunological activity. Hepatology. 2005 Nov;42(5):1028-36. doi: 10.1002/hep.20888.
• [20] Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol. 2001 Dec;35(6):749-55. doi: 10.1016/s0168-8278(01)00218-5.
• [21] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [22] Serotonin transporter mRNA expression is decreased by lamivudine and ribavirin and increased by interferon in immune cells. Scand J Immunol. 2006 Feb;63(2):106-15. doi: 10.1111/j.1365-3083.2005.01715.x.
• [23] ClinicalTrials.gov (NCT01914744) Entecavir Versus Lamivudine for Preventing the Risk of Hepatitis B Reactivation in NHL
• [24] ClinicalTrials.gov (NCT01438424) Safety and Antiviral Activity of Entecavir in Participants With Chronic Hepatitis B Following Monotherapy in Other Entecavir Trials