Details of the Drug Combination

General Information of Drug Combination (ID: DCCG3DH)

• Drug Combination Name: Sorbitol + Lamivudine
• Indication: Infection, Human Immunodeficiency Virus; Status: Phase 4 [1]
• Component Drugs:
  Sorbitol (DMAN0DE): Small molecular drug
  Lamivudine (DMI347A): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sorbitol

Disease Entry	ICD 11	Status	REF
Constipation	DD91.1	Approved	[2]

Sorbitol Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Sorbitol dehydrogenase (SORD)	DEWU03P	DHSO_HUMAN	Metabolism	[6]

Sorbitol Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Sorbitol dehydrogenase (SORD)	OTC44CR6	DHSO_HUMAN	Increases Abundance	[7]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[8]
Mitogen-activated protein kinase 9 (MAPK9)	OTCEVJ9E	MK09_HUMAN	Increases Phosphorylation	[8]
MAP kinase-activated protein kinase 2 (MAPKAPK2)	OT460SBO	MAPK2_HUMAN	Increases Activity	[9]
Mitogen-activated protein kinase 12 (MAPK12)	OTTCKE27	MK12_HUMAN	Increases Phosphorylation	[5]
Mitogen-activated protein kinase 10 (MAPK10)	OTC46VX1	MK10_HUMAN	Increases Activity	[10]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN)	OTOWDUNT	PTEN_HUMAN	Affects Localization	[11]
TAR DNA-binding protein 43 (TARDBP)	OTVOSFWW	TADBP_HUMAN	Increases Ubiquitination	[12]
Mitogen-activated protein kinase 14 (MAPK14)	OT5TCO3O	MK14_HUMAN	Increases Phosphorylation	[5]
MAP kinase-interacting serine/threonine-protein kinase 1 (MKNK1)	OTGBRJDQ	MKNK1_HUMAN	Increases Activity	[9]
Aldo-keto reductase family 1 member B1 (AKR1B1)	OTRX72TH	ALDR_HUMAN	Increases Abundance	[13]
Fragile X messenger ribonucleoprotein 1 (FMR1)	OTWEV0T5	FMR1_HUMAN	Increases Abundance	[14]

Indication(s) of Lamivudine

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

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	[15]

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	[16]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[17]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[18]

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	[19]
Phosphorylcholine transferase A (PCYT1A)	DEQYXD4	PCY1A_HUMAN	Metabolism	[20]
Phosphorylethanolamine transferase (PCYT2)	DEIX1PO	PCY2_HUMAN	Metabolism	[20]

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	[21]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Increases Uptake	[21]
BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like (BNIP3L)	OTJKOMXE	BNI3L_HUMAN	Increases Expression	[22]
G1/S-specific cyclin-E2 (CCNE2)	OTBBUKQQ	CCNE2_HUMAN	Decreases Expression	[23]
Metalloproteinase inhibitor 1 (TIMP1)	OTOXC51H	TIMP1_HUMAN	Decreases Expression	[24]
Transforming growth factor beta-1 proprotein (TGFB1)	OTV5XHVH	TGFB1_HUMAN	Decreases Expression	[24]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[25]
Collagen alpha-1(III) chain (COL3A1)	OTT1EMLM	CO3A1_HUMAN	Decreases Expression	[26]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[27]
Interstitial collagenase (MMP1)	OTI4I2V1	MMP1_HUMAN	Increases Expression	[24]
Endothelin-1 (EDN1)	OTZCACEG	EDN1_HUMAN	Increases Secretion	[22]
Cyclin-A2 (CCNA2)	OTPHHYZJ	CCNA2_HUMAN	Decreases Expression	[23]
Nitric oxide synthase 3 (NOS3)	OTLDT7NR	NOS3_HUMAN	Decreases Phosphorylation	[22]
G1/S-specific cyclin-D2 (CCND2)	OTDULQF9	CCND2_HUMAN	Decreases Expression	[23]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Increases Expression	[28]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[23]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Decreases Expression	[23]
Actin, aortic smooth muscle (ACTA2)	OTEDLG8E	ACTA_HUMAN	Decreases Expression	[26]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[21]

References

• [1] ClinicalTrials.gov (NCT02634073) A Phase IV, Open Label, 4-period Cross-over Study to Investigate a Drug Interaction Between Lamivudine and Sorbitol Oral Solutions in Healthy Volunteers
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [4] Lamivudine FDA Label
• [5] A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is a substrate for SAPKs. Biochem J. 2004 Dec 1;384(Pt 2):391-400. doi: 10.1042/BJ20041498.
• [6] Plasma concentration of iditol dehydrogenase (sorbitol dehydrogenase) in ponies treated with aflatoxin B1. Am J Vet Res. 1980 Jun;41(6):925-7.
• [7] Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet. 2020 May;52(5):473-481. doi: 10.1038/s41588-020-0615-4. Epub 2020 May 4.
• [8] Intracellular mobility and nuclear trafficking of the stress-activated kinase JNK1 are impeded by hyperosmotic stress. Biochim Biophys Acta. 2014 Feb;1843(2):253-64. doi: 10.1016/j.bbamcr.2013.10.017. Epub 2013 Nov 1.
• [9] The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem. 1998 Apr 17;273(16):9373-7. doi: 10.1074/jbc.273.16.9373.
• [10] Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. J Biol Chem. 1999 Oct 29;274(44):31150-4. doi: 10.1074/jbc.274.44.31150.
• [11] Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: Involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs. Mol Biol Cell. 2006 Sep;17(9):4002-13. doi: 10.1091/mbc.e06-05-0380. Epub 2006 Jun 28.
• [12] Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules. J Biol Chem. 2020 Jan 17;295(3):673-689. doi: 10.1074/jbc.RA119.010617. Epub 2019 Nov 28.
• [13] Aldose reductase expression as a risk factor for cataract. Chem Biol Interact. 2015 Jun 5;234:247-53. doi: 10.1016/j.cbi.2014.12.017. Epub 2014 Dec 22.
• [14] Altered redox mitochondrial biology in the neurodegenerative disorder fragile X-tremor/ataxia syndrome: use of antioxidants in precision medicine. Mol Med. 2016 Oct;22:548-559. doi: 10.2119/molmed.2016.00122. Epub 2016 Jun 30.
• [15] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [16] 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.
• [17] Genetic variants of organic cation transporter 1 (OCT1) and OCT2 significantly reduce lamivudine uptake. Biopharm Drug Dispos. 2012 Apr;33(3):170-8.
• [18] 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.
• [19] Nucleoside and nucleotide HIV reverse transcriptase inhibitors: 25 years after zidovudine. Antiviral Res. 2010 Jan;85(1):39-58.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [28] 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.