Details of the Drug Combination

General Information of Drug Combination (ID: DCE4X4G)

• Drug Combination Name: Ketorolac + Ropivacaine
• Indication: Secondary Malignant Neoplasm of Liver; Status: Phase 1 [1]
• Component Drugs:
  Ketorolac (DMI4EL5): Small molecular drug
  Ropivacaine (DMSPJG2): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Ketorolac

Disease Entry	ICD 11	Status	REF
Postoperative inflammation	1A00-CA43.1	Approved	[2]

Ketorolac Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase (COX)	TTK0943	PGH1_HUMAN; PGH2_HUMAN	Inhibitor	[5]

Ketorolac Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[6]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[6]

Ketorolac Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[7]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[7]
Endothelial PAS domain-containing protein 1 (EPAS1)	OTRE3O8U	EPAS1_HUMAN	Decreases Expression	[8]

Indication(s) of Ropivacaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[3]
Appendicitis	DB10	Approved	[4]

Ropivacaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.8 (SCN10A)	TT90XZ8	SCNAA_HUMAN	Modulator	[10]

Ropivacaine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[13]

Ropivacaine Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Apoptosis-inducing factor 1, mitochondrial (AIFM1)	OTKPWB7Q	AIFM1_HUMAN	Increases Expression	[14]
Poly polymerase 1 (PARP1)	OT310QSG	PARP1_HUMAN	Increases Cleavage	[15]
Gasdermin-D (GSDMD)	OTH39BKI	GSDMD_HUMAN	Increases Cleavage	[16]
NACHT, LRR and PYD domains-containing protein 3 (NLRP3)	OTZM6MHU	NLRP3_HUMAN	Increases Expression	[16]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Pain	DCQE80O	N. A.	Phase 4	[17]
Secondary Malignant Neoplasm of Liver	DCRDAAC	N. A.	Phase 1	[1]

References

• [1] ClinicalTrials.gov (NCT02647047) Spinal Versus Epidural Analgesia in Laparotomic Liver Surgery
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [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: 7602).
• [4] Ropivacaine FDA Label
• [5] Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H425-32.
• [6] Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics. Br J Clin Pharmacol. 2017 Sep;83(9):1966-1975.
• [7] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [8] Ibuprofen-mediated reduction of hypoxia-inducible factors HIF-1alpha and HIF-2alpha in prostate cancer cells. Clin Cancer Res. 2003 Aug 1;9(8):3150-7.
• [9] Ropivacaine inhibits proliferation?and invasion?and promotes apoptosis and autophagy in bladder cancer cells via inhibiting PI3K/AKT pathway. J Biochem Mol Toxicol. 2023 Jan;37(1):e23233. doi: 10.1002/jbt.23233. Epub 2022 Oct 3.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology. 1995 Jan;82(1):214-20.
• [12] Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther. 1998 Nov;64(5):484-91.
• [13] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [14] Effect of parthanatos on ropivacaine-induced damage in SH-SY5Y cells. Clin Exp Pharmacol Physiol. 2017 May;44(5):586-594. doi: 10.1111/1440-1681.12730.
• [15] Ectopic expression of clusterin/apolipoprotein J or Bcl-2 decreases the sensitivity of HaCaT cells to toxic effects of ropivacaine. Cell Res. 2004 Oct;14(5):415-22. doi: 10.1038/sj.cr.7290242.
• [16] Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway. J Toxicol Sci. 2023;48(3):139-148. doi: 10.2131/jts.48.139.
• [17] ClinicalTrials.gov (NCT02829944) Impact of Local Anesthetic Wound Infiltration on Postoperative Pain Following Cesarean Delivery