Details of the Drug Combination

General Information of Drug Combination (ID: DC8ESGK)

• Drug Combination Name: Propylthiouracil + Perphenazine
• Indication: Ischemic Stroke, Acute; Status: Phase 2 [1]
• Component Drugs:
  Propylthiouracil (DM6D7N8): Small molecular drug
  Perphenazine (DMA4MRX): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Propylthiouracil

Disease Entry	ICD 11	Status	REF
Hyperthyroidism	5A02	Approved	[2]
Thyroid crisis	N.A.	Approved	[3]

Propylthiouracil Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Iodothyronine deiodinase type I (DIO1)	TTU3X26	IOD1_HUMAN	Inhibitor	[7]
Thyroid peroxidase (TPO)	TT52XDZ	PERT_HUMAN	Inhibitor	[8]

Propylthiouracil Interacts with 18 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Taste receptor type 2 member 38 (TAS2R38)	OTX5MM36	T2R38_HUMAN	Increases Activity	[9]
T-box transcription factor TBX3 (TBX3)	OTM64N7K	TBX3_HUMAN	Increases Expression	[6]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[10]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Decreases Expression	[11]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Decreases Activity	[12]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Decreases Expression	[11]
Cathepsin B (CTSB)	OTP9G5QB	CATB_HUMAN	Decreases Expression	[11]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Decreases Expression	[6]
Integrin beta-5 (ITGB5)	OT21MF51	ITB5_HUMAN	Decreases Expression	[6]
Low-density lipoprotein receptor-related protein 2 (LRP2)	OTZ6W681	LRP2_HUMAN	Decreases Expression	[11]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Increases Activity	[13]
DNA-binding protein inhibitor ID-2 (ID2)	OT0U1D53	ID2_HUMAN	Increases Expression	[6]
DNA-binding protein inhibitor ID-3 (ID3)	OTUULW5Z	ID3_HUMAN	Increases Expression	[6]
Krueppel-like factor 9 (KLF9)	OTBFEJRQ	KLF9_HUMAN	Increases Expression	[6]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[10]
Carbonic anhydrase 6 (CA6)	OTIX56CJ	CAH6_HUMAN	Affects Response To Substance	[14]
Mitochondrial substrate carrier family protein ancA (ancA?)	OTTU3FKC	ADT_DICDI	Increases ADR	[15]
Basic salivary proline-rich protein 1 (PRB1)	OTV0SYMD	PRP1_HUMAN	Affects Response To Substance	[14]

Indication(s) of Perphenazine

Disease Entry	ICD 11	Status	REF
Schizophrenia	6A20	Approved	[4]
Mixed anxiety and depressive disorder	N.A.	Investigative	[5]

Perphenazine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Antagonist	[16]

Perphenazine Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[17]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[18]

Perphenazine Interacts with 7 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[19]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[20]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[21]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[19]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[19]

Perphenazine Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[22]
Troponin I, cardiac muscle (TNNI3)	OT65E12V	TNNI3_HUMAN	Increases Expression	[23]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[24]

References

• [1] ClinicalTrials.gov (NCT05762146) Networked Drug REpurposing for Mechanism-based neuroPrOtection in Acute Ischaemic STROKE
• [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: 6650).
• [3] Propylthiouracil 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: 209).
• [5] Perphenazine FDA Label
• [6] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [7] Type 1 iodothyronine deiodinase is the major source of circulating T3 in hyperthyroidism: implications for therapy. Nat Clin Pract Endocrinol Metab. 2007 Nov;3(11):740-1.
• [8] Bioinorganic chemistry in thyroid gland: effect of antithyroid drugs on peroxidase-catalyzed oxidation and iodination reactions. Bioinorg Chem Appl. 2006:23214.
• [9] Probenecid inhibits the human bitter taste receptor TAS2R16 and suppresses bitter perception of salicin. PLoS One. 2011;6(5):e20123.
• [10] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [11] Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways. Toxicol Appl Pharmacol. 2012 Apr 1;260(1):81-8. doi: 10.1016/j.taap.2012.01.029. Epub 2012 Feb 8.
• [12] Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiouracil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis. Clin Immunol. 2007 Feb;122(2):187-93. doi: 10.1016/j.clim.2006.09.011. Epub 2006 Oct 27.
• [13] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [14] Responsiveness to 6-n-propylthiouracil (PROP) is associated with salivary levels of two specific basic proline-rich proteins in humans. PLoS One. 2012;7(2):e30962. doi: 10.1371/journal.pone.0030962. Epub 2012 Feb 1.
• [15] 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.
• [16] CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine. Pharmacogenet Genomics. 2007 Nov;17(11):989-93.
• [17] Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates. J Pharm Pharmacol. 2004 Aug;56(8):967-75.
• [18] Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
• [19] Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine. Br J Clin Pharmacol. 2000 Dec;50(6):563-71.
• [20] Effect of antipsychotic drugs on human liver cytochrome P-450 (CYP) isoforms in vitro: preferential inhibition of CYP2D6. Drug Metab Dispos. 1999 Sep;27(9):1078-84.
• [21] Use of antidepressant drugs in schizophrenic patients with depression. Encephale. 2006 Mar-Apr;32(2 Pt 1):263-9.
• [22] Aripiprazole for treatment-resistant schizophrenia: results of a multicenter, randomized, double-blind, comparison study versus perphenazine. J Clin Psychiatry. 2007 Feb;68(2):213-23.
• [23] An unexpected increase of troponin I after perphenazine depot injection. Ann Pharmacother. 2004 Feb;38(2):353-4. doi: 10.1345/aph.1D234. Epub 2003 Dec 23.
• [24] Why are most phospholipidosis inducers also hERG blockers?. Arch Toxicol. 2017 Dec;91(12):3885-3895. doi: 10.1007/s00204-017-1995-9. Epub 2017 May 27.