Details of the Drug Combination

General Information of Drug Combination (ID: DC9HIUK)

• Drug Combination Name: Testosterone cypionate + Memantine
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Testosterone cypionate (DMC1TEV): N.A.
  Memantine (DMD9WSC): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 5.8
  Bliss Independence Score: 5.8
  Loewe Additivity Score: 20.15
  LHighest Single Agent (HSA) Score: 20.17

Molecular Interaction Atlas of This Drug Combination

Testosterone cypionate Interacts with 21 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[4]
Aromatase (CYP19A1)	DEQX145	CP19A_HUMAN	Metabolism	[5]
Cytochrome P450 1A1 (CYP1A1)	DE6OQ3W	CP1A1_HUMAN	Metabolism	[6]
Cytochrome P450 4B1 (CYP4B1)	DEMF740	CP4B1_HUMAN	Metabolism	[7]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[8]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[9]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[12]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[13]
Cytochrome P450 3A43 (CYP3A43)	DEO1IE3	CP343_HUMAN	Metabolism	[14]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[15]
Cholesterol 24-hydroxylase (CYP46A1)	DEKP5HX	CP46A_HUMAN	Metabolism	[16]
Cytochrome P450 2A13 (CYP2A13)	DEXZA9U	CP2AD_HUMAN	Metabolism	[17]
Steroid 5-alpha-reductase 1 (SRD5A1)	DEOG15F	S5A1_HUMAN	Metabolism	[18]
Steroid 5-alpha-reductase 2 (SRD5A2)	DEPTJ3D	S5A2_HUMAN	Metabolism	[18]
Steroid 5-alpha-reductase 3 (SRD5A3)	DEZGVDW	PORED_HUMAN	Metabolism	[18]
Farnesol dehydrogenase (AKR1B15)	DER0XCH	AK1BF_HUMAN	Metabolism	[19]
Dehydrogenase/reductase retSDR3 (HSD17B14)	DEGTB1K	DHB14_HUMAN	Metabolism	[20]
Cytochrome P450 MEG (cyp106)	DEZ1H4L	CPXM_BACME	Metabolism	[21], [22]
Cytochrome P450 154C2 (cyp154)	DEHDW40	A0A345AH95_STRSQ	Metabolism	[23], [24]

Indication(s) of Memantine

Disease Entry	ICD 11	Status	REF
Alzheimer disease	8A20	Approved	[2]
Asperger syndrome	N.A.	Approved	[3]
Glioblastoma	2A00	Approved	[3]

Memantine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
N-methyl-D-aspartate receptor (NMDAR)	TT9IK2Z	NOUNIPROTAC	Modulator	[25]

Memantine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[26]

Memantine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Decreases Expression	[27]
Myc proto-oncogene protein (MYC)	OTPV5LUK	MYC_HUMAN	Decreases Expression	[27]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[27]
Cyclin-dependent kinase 4 (CDK4)	OT7EP05T	CDK4_HUMAN	Increases Expression	[27]
G1/S-specific cyclin-D1 (CCND1)	OT8HPTKJ	CCND1_HUMAN	Decreases Expression	[27]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Expression	[27]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Expression	[27]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Affects Expression	[27]

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] 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: 4253).
• [3] Memantine FDA Label
• [4] Digging deeper into CYP3A testosterone metabolism: kinetic, regioselectivity, and stereoselectivity differences between CYP3A4/5 and CYP3A7. Drug Metab Dispos. 2017 Dec;45(12):1266-1275.
• [5] Loss of aromatase cytochrome P450 function as a risk factor for Parkinson's disease? Brain Res Rev. 2008 Mar;57(2):431-43.
• [6] Allelic variants of human cytochrome P450 1A1 (CYP1A1): effect of T461N and I462V substitutions on steroid hydroxylase specificity. Pharmacogenetics. 2000 Aug;10(6):519-30.
• [7] Steroid hormone hydroxylase specificities of eleven cDNA-expressed human cytochrome P450s. Arch Biochem Biophys. 1991 Oct;290(1):160-6.
• [8] In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos. 2003 Jul;31(7):938-44.
• [9] Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus. Res Commun Mol Pathol Pharmacol. 1998 Apr;100(1):15-28.
• [10] Role of cytochrome P450 2C8 in drug metabolism and interactions. Pharmacol Rev. 2016 Jan;68(1):168-241.
• [11] Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006 May;34(5):734-7.
• [12] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [13] Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes. Arch Biochem Biophys. 1997 Oct 1;346(1):161-9.
• [14] cDNA cloning and initial characterization of CYP3A43, a novel human cytochrome P450. Mol Pharmacol. 2001 Feb;59(2):386-92.
• [15] Catalytic properties of polymorphic human cytochrome P450 1B1 variants. Carcinogenesis. 1999 Aug;20(8):1607-13.
• [16] Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry. 2003 Dec 9;42(48):14284-92.
• [17] Effects of 8-methoxypsoralen on cytochrome P450 2A13. Carcinogenesis. 2005 Mar;26(3):621-9.
• [18] Molecular analysis of the SRD5A1 and SRD5A2 genes in patients with benign prostatic hyperplasia with regard to metabolic parameters and selected hormone levels. Int J Environ Res Public Health. 2017 Oct 30;14(11).
• [19] Aldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates. J Biol Chem. 2015 Mar 6;290(10):6531-45.
• [20] Expression patterns of 17beta-hydroxysteroid dehydrogenase 14 in human tissues. Horm Metab Res. 2012 Dec;44(13):949-56.
• [21] acillus megaterium SF185 spores exert protective effects against oxidative stress in vivo and in vitro. Sci Rep. 2019 Aug 19;9(1):12082.
• [22] A Novel NADPH-dependent flavoprotein reductase from Bacillus megaterium acts as an efficient cytochrome P450 reductase. J Biotechnol. 2016 Aug 10;231:83-94.
• [23] Regio- and stereoselective hydroxylation of testosterone by a novel cytochrome P450 154C2 from Streptomyces avermitilis. Biochem Biophys Res Commun. 2020 Feb 5;522(2):355-361.
• [24] The metagenome of Caracolus marginella gut microbiome using culture independent approaches and shotgun sequencing. Data Brief. 2017 Nov 22;16:501-505.
• [25] The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical evidence. Int J Geriatr Psychiatry. 2003 Sep;18(Suppl 1):S23-32.
• [26] Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol. 1998 Aug;54(2):342-52.
• [27] Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells. Hum Exp Toxicol. 2018 Sep;37(9):953-958. doi: 10.1177/0960327117747025. Epub 2017 Dec 11.