Details of the Drug Combination

General Information of Drug Combination (ID: DCMBRZA)

• Drug Combination Name: Propylthiouracil + Levothyroxine
• Indication: Paediatric Thyrotoxicosis; Status: Phase 1 [1]
• Component Drugs:
  Propylthiouracil (DM6D7N8): Small molecular drug
  Levothyroxine (DMHN027): 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 Levothyroxine

Disease Entry	ICD 11	Status	REF
Congenital hypothyroidism	N.A.	Approved	[4]
Edema	MG29	Approved	[4]
Goiter	N.A.	Approved	[4]
Hashimoto thyroiditis	N.A.	Approved	[4]
Hyperlipidemia	5C80.Z	Approved	[4]
Hypothyroidism	5A00	Approved	[5]
Thyroid cancer	2D10	Approved	[4]

Levothyroxine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Thyroid hormone receptor alpha (THRA)	TTTSEPU	THA_HUMAN	Antagonist	[16]

Levothyroxine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[17]
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[18]
Organic anion transporting polypeptide 1C1 (SLCO1C1)	DTPYCQ4	SO1C1_HUMAN	Substrate	[19]

Levothyroxine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[21]

References

• [1] ClinicalTrials.gov (NCT01436994) Antithyroid Drug Treatment of Thyrotoxicosis in Young People
• [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] Levothyroxine 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: 4627).
• [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] Thyroid hormone resistance and pituitary enlargement after thyroid ablation in a woman on levothyroxine treatment. Thyroid. 2008 Oct;18(10):1119-23.
• [17] Identification of a novel gene family encoding human liver-specific organic anion transporter LST-1. J Biol Chem. 1999 Jun 11;274(24):17159-63.
• [18] Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001 May;142(5):2005-12.
• [19] Identification of a novel human organic anion transporting polypeptide as a high affinity thyroxine transporter. Mol Endocrinol. 2002 Oct;16(10):2283-96.
• [20] [Metabolic interaction between psychopharmaceuticals. Probable cause of exacerbation of hypothyroidism according to a case report]. Lakartidningen. 2002 Jun 20;99(25):2854-6.
• [21] Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.