Details of the Drug Combination

General Information of Drug Combination (ID: DC04760)

• Drug Combination Name: Alprazolam + Caffeine
• Indication: Psychotropic Drugs Effects; Status: Phase 1 [1]
• Component Drugs:
  Alprazolam (DMC7XDN): Small molecular drug
  Caffeine (DMKBJWP): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Alprazolam

Disease Entry	ICD 11	Status	REF
Anxiety	N.A.	Approved	[2]
Anxiety disorder	6B00-6B0Z	Approved	[3]
Panic disorder	6B01	Approved	[2]
Epilepsy	8A60-8A68	Phase 2	[4]
Mixed anxiety and depressive disorder	N.A.	Investigative	[2]

Alprazolam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Agonist	[7]

Alprazolam Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[8]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[9]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]

Alprazolam Interacts with 5 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A5 (CYP3A5)	OTSXFBXB	CP3A5_HUMAN	Increases Hydroxylation	[9]
Translocator protein (TSPO)	OTSU7ESK	TSPO_HUMAN	Increases ADR	[12]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Secretion	[13]
Platelet-activating factor receptor (PTAFR)	OT2133DF	PTAFR_HUMAN	Increases ADR	[12]
Peptidyl-prolyl cis-trans isomerase A (PPIA)	OTHJMWQQ	PPIA_HUMAN	Increases Hydroxylation	[14]

Indication(s) of Caffeine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[5]
Back pain	ME84.Z	Approved	[5]
Cluster headache	8A81.0	Approved	[5]
Common cold	CA00	Approved	[5]
Dysmenorrhea	GA34.3	Approved	[5]
Headache	8A80-8A84	Approved	[5]
Migraine disorder	N.A.	Approved	[5]
Orthostatic hypotension	BA21	Approved	[6]
Pain	MG30-MG3Z	Approved	[5]

Caffeine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adenosine A2a receptor (ADORA2A)	TTM2AOE	AA2AR_HUMAN	Antagonist	[15]
Adenosine A1 receptor (ADORA1)	TTK25J1	AA1R_HUMAN	Antagonist	[15]

Caffeine Interacts with 8 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[17]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[18]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[19]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[22]

Caffeine Interacts with 2 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Increases ADR	[23]
Metallothionein-1A (MT1A)	OTKBH52X	MT1A_HUMAN	Increases ADR	[12]

References

• [1] ClinicalTrials.gov (NCT01747590) Imaging the Effects of Zolpidem and Alprazolam in Healthy Volunteers at 3T
• [2] Alprazolam 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: 7111).
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Caffeine FDA Label
• [6] 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: 407).
• [7] Comparison of five benzodiazepine-receptor agonists on buprenorphine-induced mu-opioid receptor regulation. J Pharmacol Sci. 2009 May;110(1):36-46.
• [8] No relevant interaction with alprazolam, caffeine, tolbutamide, and digoxin by treatment with a low-hyperforin St John's wort extract. Planta Med. 2005 Apr;71(4):331-7.
• [9] Identification and phenotype characterization of two CYP3A haplotypes causing different enzymatic capacity in fetal livers. Clin Pharmacol Ther. 2005 Apr;77(4):259-70.
• [10] Drug Interactions Flockhart Table
• [11] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [12] 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.
• [13] The effect of alprazolam on serum cortisol and luteinizing hormone pulsatility in normal women and in women with stress-related anovulation. J Clin Endocrinol Metab. 1995 Mar;80(3):818-23. doi: 10.1210/jcem.80.3.7883836.
• [14] Alprazolam as a probe for CYP3A using a single blood sample: pharmacokinetics of parent drug, and of alpha- and 4-hydroxy metabolites in healthy subjects. Eur J Clin Pharmacol. 2005 Apr;61(2):113-8.
• [15] Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72.
• [16] Effect of cytochrome P450 (CYP) inducers on caffeine metabolism in the rat. Pharmacol Rep. 2007 May-Jun;59(3):296-305.
• [17] A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther. 1993 Aug;54(2):134-41.
• [18] Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo. J Clin Psychopharmacol. 1998 Jun;18(3):198-207.
• [19] CYP2E1 active site residues in substrate recognition sequence 5 identified by photoaffinity labeling and homology modeling. Arch Biochem Biophys. 2007 Mar 1;459(1):59-69.
• [20] PharmGKB summary: caffeine pathway. Pharmacogenet Genomics. 2012 May;22(5):389-95.
• [21] Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline. Xenobiotica. 2013 Dec;43(12):1037-42.
• [22] Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos. 1997 May;25(5):617-22.
• [23] Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. doi: 10.1001/jama.295.10.1135.