Details of the Drug Combination

General Information of Drug Combination (ID: DCFEJH6)

• Drug Combination Name: Metyrapone + Oxazepam
• Indication: Cocaine Dependence; Status: Phase 1 [1]
• Component Drugs:
  Metyrapone (DMI7FVQ): Small molecular drug
  Oxazepam (DMXNZM4): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metyrapone

Disease Entry	ICD 11	Status	REF
Cushing disease	5A70	Approved	[2]

Metyrapone Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Steroid 11-beta-hydroxylase (CYP11B1)	TTIQUX7	C11B1_HUMAN	Inhibitor	[5]

Metyrapone Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[6]
11-beta-hydroxysteroid dehydrogenase 1 (HSD11B1)	OTO7FJA9	DHI1_HUMAN	Decreases Activity	[7]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[7]
17-beta-hydroxysteroid dehydrogenase type 1 (HSD17B1)	OT6EBDHM	DHB1_HUMAN	Decreases Expression	[8]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2 (HSD3B2)	OT02MSKN	3BHS2_HUMAN	Decreases Expression	[8]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Increases Expression	[9]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[10]
Pro-opiomelanocortin (POMC)	OTV41F7T	COLI_HUMAN	Increases Expression	[11]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Increases Activity	[10]
Dehydrogenase/reductase SDR family member 7 (DHRS7)	OTV729DT	DHRS7_HUMAN	Increases Reduction	[12]

Indication(s) of Oxazepam

Disease Entry	ICD 11	Status	REF
Alcohol withdrawal delirium	N.A.	Approved	[3]
Anxiety	N.A.	Approved	[3]
Anxiety disorder	6B00-6B0Z	Approved	[4]

Oxazepam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Agonist	[15]

Oxazepam Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[18]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]
Cytochrome P450 3A43 (CYP3A43)	DEO1IE3	CP343_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[14]

References

• [1] ClinicalTrials.gov (NCT00567814) A Placebo-Controlled Study of a Combination of Metyrapone and Oxazepam in Cocaine Addiction
• [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: 5224).
• [3] Oxazepam FDA Label
• [4] 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: 7253).
• [5] Effects of 3-MeSO2-DDE and some CYP inhibitors on glucocorticoid steroidogenesis in the H295R human adrenocortical carcinoma cell line. Toxicol In Vitro. 2002 Apr;16(2):113-21.
• [6] A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro. Xenobiotica. 1999 Mar;29(3):269-79.
• [7] In the search for specific inhibitors of human 11beta-hydroxysteroid-dehydrogenases (11beta-HSDs): chenodeoxycholic acid selectively inhibits 11beta-HSD-I. Eur J Endocrinol. 2000 Feb;142(2):200-7.
• [8] The H295R system for evaluation of endocrine-disrupting effects. Ecotoxicol Environ Saf. 2006 Nov;65(3):293-305.
• [9] Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab Dispos. 2003 Nov;31(11):1296-9. doi: 10.1124/dmd.31.11.1296.
• [10] In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest. 2006 Sep;36(9):647-53. doi: 10.1111/j.1365-2362.2006.01700.x.
• [11] Mineralocorticoid receptor function in posttraumatic stress disorder after pretreatment with metyrapone. Biol Psychiatry. 2006 Oct 1;60(7):784-7. doi: 10.1016/j.biopsych.2006.01.014. Epub 2006 Mar 29.
• [12] Biochemical properties of human dehydrogenase/reductase (SDR family) member 7. Chem Biol Interact. 2014 Jan 25;207:52-7. doi: 10.1016/j.cbi.2013.11.003. Epub 2013 Nov 16.
• [13] (S)oxazepam glucuronidation is inhibited by ketoprofen and other substrates of UGT2B7. Pharmacogenetics. 1995 Feb;5(1):43-9. doi: 10.1097/00008571-199502000-00005.
• [14] Stereoselective conjugation of oxazepam by human UDP-glucuronosyltransferases (UGTs): S-oxazepam is glucuronidated by UGT2B15, while R-oxazepam is glucuronidated by UGT2B7 and UGT1A9. Drug Metab Dispos. 2002 Nov;30(11):1257-65.
• [15] Effects of the combination of metyrapone and oxazepam on cocaine and food self-administration in rats. Pharmacol Biochem Behav. 2008 Nov;91(1):181-9.
• [16] Bioreactor systems in drug metabolism: synthesis of cytochrome P450-generated metabolites. Metab Eng. 2000 Apr;2(2):115-25.
• [17] Evidence for oxazepam as an in vivo probe of UGT2B15: oxazepam clearance is reduced by UGT2B15 D85Y polymorphism but unaffected by UGT2B17 deletion. Br J Clin Pharmacol. 2009 Nov;68(5):721-30.
• [18] Cytochrome P450 enzyme activity and protein expression in primary porcine enterocyte and hepatocyte cultures. Xenobiotica. 2000 Jan;30(1):27-46.