Details of the Drug Combination

General Information of Drug Combination (ID: DCZB71G)

• Drug Combination Name: Metoclopramide + Ketorolac
• Indication: Probable Migraine; Status: Phase 1 [1]
• Component Drugs:
  Metoclopramide (DMFA5MY): Small molecular drug
  Ketorolac (DMI4EL5): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metoclopramide

Disease Entry	ICD 11	Status	REF
Nausea	MD90	Approved	[2]

Metoclopramide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Antagonist	[4]

Metoclopramide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[5]

Metoclopramide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[6]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]

Metoclopramide Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[7]
Retinal dehydrogenase 2 (ALDH1A2)	OTJB560Z	AL1A2_HUMAN	Decreases Expression	[8]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[9]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[10]
Pro-glucagon (GCG)	OTXU08VF	GLUC_HUMAN	Increases Secretion	[11]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[12]
Gastric inhibitory polypeptide (GIP)	OTUFSTG9	GIP_HUMAN	Increases Secretion	[11]
5-hydroxytryptamine receptor 3A (HTR3A)	OTAIV1AK	5HT3A_HUMAN	Decreases Activity	[13]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Response	[15]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Response	[16]

Indication(s) of Ketorolac

Disease Entry	ICD 11	Status	REF
Postoperative inflammation	1A00-CA43.1	Approved	[3]

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	[17]

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	[18]
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[18]

Ketorolac Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Prostaglandin G/H synthase 1 (PTGS1)	OTHCRLEC	PGH1_HUMAN	Decreases Expression	[19]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[19]
HLA class I histocompatibility antigen, A alpha chain (HLA-A)	OTAH14LU	HLAA_HUMAN	Affects Expression	[20]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[20]
HLA class I histocompatibility antigen, alpha chain G (HLA-G)	OTMLK1KN	HLAG_HUMAN	Affects Expression	[20]
Hypoxia-inducible factor 1-alpha (HIF1A)	OTADSC03	HIF1A_HUMAN	Decreases Expression	[21]
Endothelial PAS domain-containing protein 1 (EPAS1)	OTRE3O8U	EPAS1_HUMAN	Decreases Expression	[21]

References

• [1] ClinicalTrials.gov (NCT01596166) Intravenous Ketorolac and Metoclopramide for Pediatric Migraine in the Emergency Department
• [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: 241).
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats. Eur J Pharmacol. 2008 Jun 10;587(1-3):181-6.
• [5] 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.
• [6] Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6. Xenobiotica. 2014 Apr;44(4):309-319.
• [7] Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology. 2005 Apr;74(1):31-6. doi: 10.1159/000083234. Epub 2005 Jan 7.
• [8] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [9] Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. J Clin Endocrinol Metab. 1987 Mar;64(3):508-12. doi: 10.1210/jcem-64-3-508.
• [10] Growth hormone and prolactin secretion after metoclopramide administration (DA2 receptor blockade) in fertile women. Horm Metab Res. 2001 Sep;33(9):536-9. doi: 10.1055/s-2001-17214.
• [11] Effects of metoclopramide on duodenal motility and flow events, glucose absorption, and incretin hormone release in response to intraduodenal glucose infusion. Am J Physiol Gastrointest Liver Physiol. 2010 Dec;299(6):G1326-33. doi: 10.1152/ajpgi.00476.2009. Epub 2010 Sep 9.
• [12] Effect of drugs interacting with the dopaminergic receptors on glucose levels and insulin release in healthy and type 2 diabetic subjects. Am J Ther. 2008 Jul-Aug;15(4):397-402. doi: 10.1097/MJT.0b013e318160c353.
• [13] Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers. Br J Pharmacol. 2005 Oct;146(4):543-52. doi: 10.1038/sj.bjp.0706351.
• [14] Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
• [15] Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy. Jpn J Clin Oncol. 2011 Oct;41(10):1168-76. doi: 10.1093/jjco/hyr117. Epub 2011 Aug 11.
• [16] Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters. J Clin Gastroenterol. 2012 Jul;46(6):494-503. doi: 10.1097/MCG.0b013e3182522624.
• [17] Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H425-32.
• [18] Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics. Br J Clin Pharmacol. 2017 Sep;83(9):1966-1975.
• [19] Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain. 2007 Jun;129(3):279-86.
• [20] 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.
• [21] 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.