Details of the Drug Combination

General Information of Drug Combination (ID: DCZ0DFM)

• Drug Combination Name: Biperiden + Caffeine
• Indication: Cocaine Related Disorders; Status: Phase 1 [1]
• Component Drugs:
  Biperiden (DME78OA): Small molecular drug
  Caffeine (DMKBJWP): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Biperiden

Disease Entry	ICD 11	Status	REF
Parkinson disease	8A00.0	Approved	[2]
Parkinsonian disorder	N.A.	Approved	[3]
Postencephalitic Parkinson disease	N.A.	Approved	[3]

Biperiden Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Muscarinic acetylcholine receptor M1 (CHRM1)	TTZ9SOR	ACM1_HUMAN	Antagonist	[6]

Biperiden Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[7]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[7]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[7]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[7]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[7]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Activity	[8]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[7]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[7]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[7]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[7]

Indication(s) of Caffeine

Disease Entry	ICD 11	Status	REF
Allergic rhinitis	CA08.0	Approved	[4]
Back pain	ME84.Z	Approved	[4]
Cluster headache	8A81.0	Approved	[4]
Common cold	CA00	Approved	[4]
Dysmenorrhea	GA34.3	Approved	[4]
Headache	8A80-8A84	Approved	[4]
Migraine disorder	N.A.	Approved	[4]
Orthostatic hypotension	BA21	Approved	[5]
Pain	MG30-MG3Z	Approved	[4]

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	[9]
Adenosine A1 receptor (ADORA1)	TTK25J1	AA1R_HUMAN	Antagonist	[9]

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	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
RNA cytidine acetyltransferase (hALP)	DEZV4AP	NAT10_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[14]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[16]
Cytochrome P450 1B1 (CYP1B1)	DE9QHP6	CP1B1_HUMAN	Metabolism	[17]

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	[18]
Metallothionein-1A (MT1A)	OTKBH52X	MT1A_HUMAN	Increases ADR	[19]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Cocaine Dependence	DC76NZW	N. A.	Phase 1	[20]

References

• [1] ClinicalTrials.gov (NCT00495092) Efficacy of Caffeine, With and Without Biperiden, in the Detoxification of Cocaine Dependent Patients
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Biperiden FDA Label
• [4] Caffeine FDA Label
• [5] 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).
• [6] Evaluation of in vivo binding properties of 3H-NMPB and 3H-QNB in mouse brain. J Neural Transm. 1999;106(7-8):583-92.
• [7] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [8] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [9] Caffeine as a psychomotor stimulant: mechanism of action. Cell Mol Life Sci. 2004 Apr;61(7-8):857-72.
• [10] Effect of cytochrome P450 (CYP) inducers on caffeine metabolism in the rat. Pharmacol Rep. 2007 May-Jun;59(3):296-305.
• [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] A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther. 1993 Aug;54(2):134-41.
• [13] 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.
• [14] 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.
• [15] PharmGKB summary: caffeine pathway. Pharmacogenet Genomics. 2012 May;22(5):389-95.
• [16] Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline. Xenobiotica. 2013 Dec;43(12):1037-42.
• [17] Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos. 1997 May;25(5):617-22.
• [18] Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 2006 Mar 8;295(10):1135-41. doi: 10.1001/jama.295.10.1135.
• [19] 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.
• [20] ClinicalTrials.gov (NCT00495183) Efficacy of Caffeine, With and Without Biperiden, as a Maintenance Treatment for Cocaine Dependence