Details of the Drug Combination

General Information of Drug Combination (ID: DCAZJA9)

• Drug Combination Name: Trihexyphenidyl + Ezetimibe
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Trihexyphenidyl (DMB19L8): Small molecular drug
  Ezetimibe (DM7A8TW): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 16.46
  Bliss Independence Score: 16.46
  Loewe Additivity Score: 30.47
  LHighest Single Agent (HSA) Score: 30.47

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Trihexyphenidyl

Disease Entry	ICD 11	Status	REF
Dystonia	8A02	Approved	[2]
Parkinson disease	8A00.0	Approved	[2]
Parkinsonian disorder	N.A.	Approved	[3]
Postencephalitic Parkinson disease	N.A.	Approved	[3]
Obesity	5B81	Investigative	[4]

Trihexyphenidyl Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Muscarinic acetylcholine receptor M1 (CHRM1)	TTZ9SOR	ACM1_HUMAN	Antagonist	[7]
Adrenergic receptor beta-3 (ADRB3)	TTMXGCW	ADRB3_HUMAN	Agonist	[4]

Trihexyphenidyl Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Increases Expression	[8]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[8]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[8]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[8]
Hepatocyte growth factor receptor (MET)	OT7K55MU	MET_HUMAN	Increases Expression	[8]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[8]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Increases Expression	[8]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[8]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Increases Expression	[8]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[8]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[8]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Increases Expression	[8]
Apolipoprotein E (APOE)	OTFOWL2H	APOE_HUMAN	Increases Response To Substance	[9]

Indication(s) of Ezetimibe

Disease Entry	ICD 11	Status	REF
Atherosclerosis	BD40	Approved	[5]
Hypercholesterolaemia	5C80.0	Approved	[6]
Hyperlipidemia	5C80.Z	Approved	[5]
Hyperlipidemia, familial combined, LPL related	N.A.	Approved	[5]
Non-alcoholic fatty liver disease	DB92	Approved	[5]
Type-1/2 diabetes	5A10-5A11	Approved	[5]

Ezetimibe Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Niemann-Pick C1-like protein 1 (NPC1L1)	TTPD1CN	NPCL1_HUMAN	Inhibitor	[11]

Ezetimibe Interacts with 6 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Multidrug resistance-associated protein 2 (ABCC2)	DTFI42L	MRP2_HUMAN	Substrate	[12]
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[13]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[14]
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[15]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[14]
Bile salt export pump (ABCB11)	DTJ0EW4	ABCBB_HUMAN	Substrate	[16]

Ezetimibe Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A3 (UGT1A3)	DEF2WXN	UD13_HUMAN	Metabolism	[18]
UDP-glucuronosyltransferase 2B15 (UGT2B15)	DENZ6B1	UDB15_HUMAN	Metabolism	[17]

Ezetimibe Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[16]
3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)	OTRT3F3U	HMDH_HUMAN	Increases Activity	[19]
Phospholipid-transporting ATPase ABCA1 (ABCA1)	OT94G6BQ	ABCA1_HUMAN	Decreases Expression	[20]
Retinoic acid receptor gamma (RARG)	OT8LHMDH	RARG_HUMAN	Decreases Expression	[20]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Decreases Expression	[20]
Oxysterols receptor LXR-beta (NR1H2)	OT4APA60	NR1H2_HUMAN	Decreases Expression	[20]
Sterol regulatory element-binding protein 2 (SREBF2)	OTBXUNPL	SRBP2_HUMAN	Decreases Expression	[20]
Scavenger receptor class B member 1 (SCARB1)	OTAE1UA1	SCRB1_HUMAN	Decreases Expression	[20]
NPC1-like intracellular cholesterol transporter 1 (NPC1L1)	OT6GWW1P	NPCL1_HUMAN	Decreases Response To Substance	[21]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [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: 7315).
• [3] Trihexyphenidyl FDA Label
• [4] Obesity: pathophysiology and clinical management. Curr Med Chem. 2009;16(4):506-21.
• [5] Ezetimibe 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: 6816).
• [7] The role of M1 muscarinic cholinergic receptors in the discriminative stimulus properties of N-desmethylclozapine and the atypical antipsychotic dr... Psychopharmacology (Berl). 2009 Apr;203(2):295-301.
• [8] 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.
• [9] Increased mental slowing associated with the APOE epsilon4 allele after trihexyphenidyl oral anticholinergic challenge in healthy elderly. Am J Geriatr Psychiatry. 2008 Feb;16(2):116-24. doi: 10.1097/JGP.0b013e31815aff75.
• [10] Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos. 2004 Mar;32(3):314-20.
• [11] Update on patented cholesterol absorption inhibitors. Expert Opin Ther Pat. 2009 Aug;19(8):1083-107.
• [12] Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans. Clin Pharmacol Ther. 2006 Mar;79(3):206-17.
• [13] Pharmacokinetic and pharmacodynamic interactions between the immunosuppressant sirolimus and the lipid-lowering drug ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2010 Jun;87(6):663-7.
• [14] Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009 Aug;37(8):1698-702.
• [15] A LC-MS/MS method to quantify the novel cholesterol lowering drug ezetimibe in human serum, urine and feces in healthy subjects genotyped for SLCO1B1. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Jan 2;830(1):143-50.
• [16] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [17] Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44(5):467-94.
• [18] Drug interactions between the immunosuppressant tacrolimus and the cholesterol absorption inhibitor ezetimibe in healthy volunteers. Clin Pharmacol Ther. 2011 Apr;89(4):524-8.
• [19] Effects of ezetimibe and/or simvastatin on LDL receptor protein expression and on LDL receptor and HMG-CoA reductase gene expression: a randomized trial in healthy men. Atherosclerosis. 2008 May;198(1):198-207.
• [20] Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. J Nutr. 2005 Oct;135(10):2305-12. doi: 10.1093/jn/135.10.2305.
• [21] Compound heterozygosity for two non-synonymous polymorphisms in NPC1L1 in a non-responder to ezetimibe. Clin Genet. 2005 Feb;67(2):175-7. doi: 10.1111/j.1399-0004.2004.00388.x.