Details of the Drug Combination

General Information of Drug Combination (ID: DC56OQJ)

• Drug Combination Name: Sitagliptin + Maprotiline
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Sitagliptin (DMGDKXN): Small molecular drug
  Maprotiline (DMPWB7T): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 3.66
  Bliss Independence Score: 3.66
  Loewe Additivity Score: 4.63
  LHighest Single Agent (HSA) Score: 4.63

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Sitagliptin

Disease Entry	ICD 11	Status	REF
Cystic fibrosis	CA25	Approved	[2]
Non-insulin dependent diabetes	5A11	Approved	[2]
Renal hypoplasia	N.A.	Approved	[2]
Type-2 diabetes	5A11	Approved	[3]
Peripheral arterial disease	BD4Z	Phase 1/2	[4]

Sitagliptin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dipeptidyl peptidase 4 (DPP-4)	TTDIGC1	DPP4_HUMAN	Inhibitor	[7]

Sitagliptin Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[8]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[9]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[10]

Sitagliptin Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[11]

Indication(s) of Maprotiline

Disease Entry	ICD 11	Status	REF
Depression	6A70-6A7Z	Approved	[5]
Major depressive disorder	6A70.3	Approved	[6]
Mixed anxiety and depressive disorder	N.A.	Investigative	[5]

Maprotiline Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Norepinephrine transporter (NET)	TTAWNKZ	SC6A2_HUMAN	Inhibitor	[12]

Maprotiline Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]

Maprotiline Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Increases ADR	[14]
Beclin-1 (BECN1)	OT4X293M	BECN1_HUMAN	Increases Expression	[15]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Sitagliptin 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: 6286).
• [4] ClinicalTrials.gov (NCT01619332) Clinical Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LEZ763. U.S. National Institutes of Health.
• [5] Maprotiline FDA Label
• [6] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [7] Novel therapeutics for type 2 diabetes: incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol Ther. 2009 Oct;124(1):113-38.
• [8] Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
• [9] 265 effect of dietary cholesterol on gallbladder bile lithogenicity and gene expression in the enterohepatic axis of non-obese gallstone and control women. Journal of Hepatology, 2009, 50(09):S105-S106.
• [10] Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007 May;321(2):673-83.
• [11] Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab. 2010 Aug;12(8):648-58.
• [12] Effect of pharmacologically selective antidepressants on serotonin uptake in rat platelets. Gen Physiol Biophys. 2005 Mar;24(1):113-28.
• [13] Cytochrome P450 enzymes contributing to demethylation of maprotiline in man. Pharmacol Toxicol. 2002 Mar;90(3):144-9.
• [14] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [15] The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt's lymphoma. Int J Cancer. 2011 Apr 1;128(7):1712-23. doi: 10.1002/ijc.25477. Epub 2010 May 25.