Details of the Drug Combination

General Information of Drug Combination (ID: DC7X5RP)

• Drug Combination Name: Dextroamphetamine + Modafinil
• Indication: Cocaine-Related Disorders; Status: Phase 1 [1]
• Component Drugs:
  Dextroamphetamine (DMMIHVP): Small molecular drug
  Modafinil (DMYILBE): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dextroamphetamine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Narcolepsy	7A20	Approved	[2]

Dextroamphetamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Trace amine-associated receptor-1 (TAAR1)	TTIU98M	TAAR1_HUMAN	Modulator	[7]

Dextroamphetamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[8]

Dextroamphetamine Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[9]
Sodium-dependent noradrenaline transporter (SLC6A2)	OTMHQJMP	SC6A2_HUMAN	Decreases Activity	[10]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Expression	[9]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Decreases Activity	[10]
Synaptic vesicular amine transporter (SLC18A2)	OTUOMMM6	VMAT2_HUMAN	Affects Binding	[11]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[9]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[9]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[9]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[9]
Disrupted in schizophrenia 1 protein (DISC1)	OT43AW4H	DISC1_HUMAN	Increases Response To Substance	[12]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[13]
Glial cell line-derived neurotrophic factor (GDNF)	OT8ICC4Z	GDNF_HUMAN	Affects Response To Substance	[14]
Brain-derived neurotrophic factor (BDNF)	OTLGH7EW	BDNF_HUMAN	Affects Response To Substance	[15]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Affects Response To Substance	[16]

Indication(s) of Modafinil

Disease Entry	ICD 11	Status	REF
Malignant glioma	2A00.0	Approved	[4]
Methamphetamine dependence	6C46.2	Approved	[4]
Narcolepsy	7A20	Approved	[2]
Pain	MG30-MG3Z	Approved	[4]
Postpoliomyelitis syndrome	N.A.	Approved	[4]
Traumatic brain injury	NA07.Z	Approved	[4]
Bipolar disorder	6A60	Phase 4	[5]
Brain injury	NA07.Z	Investigative	[6]

Modafinil Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine transporter (DAT)	TTVBI8W	SC6A3_HUMAN	Modulator	[17]

Modafinil Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[18]

Modafinil Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Affects Response To Substance	[19]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Affects Response To Substance	[20]

References

• [1] ClinicalTrials.gov (NCT00218062) Effectiveness of Modafinil and D-amphetamine in Treating Cocaine Dependent Individuals
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Dextroamphetamine FDA Label
• [4] Modafinil FDA Label
• [5] ClinicalTrials.gov (NCT01965925) Targeting Circadian and Cognitive Dysfunction in Bipolar Disorder With Modafinil. U.S. National Institutes of Health.
• [6] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [7] Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014 Oct;85:499-507.
• [8] Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999 Jul;29(7):719-32.
• [9] An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol. 2013 Dec;87(12):2165-85. doi: 10.1007/s00204-013-1082-9. Epub 2013 Jul 3.
• [10] Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR. Neurotoxicology. 2019 May;72:95-100. doi: 10.1016/j.neuro.2019.02.011. Epub 2019 Feb 15.
• [11] Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res. 1994 Mar;22(1-4):219-26. doi: 10.1016/0169-328x(94)90050-7.
• [12] Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry. 2016 Nov;21(11):1561-1572. doi: 10.1038/mp.2015.194. Epub 2016 Jan 12.
• [13] Serotonin transporter genotype and acute subjective response to amphetamine. Am J Addict. 2006 Sep-Oct;15(5):327-35. doi: 10.1080/10550490600859868.
• [14] Behavioral improvement and dopamine release in a Parkinsonian rat model. Neurosci Lett. 2002 Sep 13;330(1):5-8. doi: 10.1016/s0304-3940(02)00672-9.
• [15] An association study of the brain-derived neurotrophic factor Val66Met polymorphism and amphetamine response. Am J Med Genet B Neuropsychiatr Genet. 2006 Sep 5;141B(6):576-83. doi: 10.1002/ajmg.b.30327.
• [16] Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A. 2003 May 13;100(10):6186-91. doi: 10.1073/pnas.0931309100. Epub 2003 Apr 25.
• [17] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [18] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [19] Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT. Sleep. 2010 Aug;33(8):1027-35. doi: 10.1093/sleep/33.8.1027.
• [20] Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans. J Neurosci. 2014 Jan 8;34(2):566-73. doi: 10.1523/JNEUROSCI.4128-13.2014.