Details of Drug Interaction | MecDDI

Drug General Information (ID: DDITA6W7X0)
Drug Name			Clopidogrel		Drug Info		Loperamide		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiplatelet Agents				Antidiarrheals
Structure

Mechanism of Clopidogrel-Loperamide Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Clopidogrel				Loperamide
Mechanism		CYP450 2C8 inhibitor				CYP450 2C8 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2C8				× Structure Sequence MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV
		Gene Name		CYP2C8
		Uniprot ID		CP2C8_HUMAN
		KEGG Pathway		hsa:1558
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316). Click to Show/Hide
Mechanism Description		Decreased metabolism of Loperamide caused by Clopidogrel mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is recommended if loperamide is used with drugs that enhance its gastrointestinal absorption or inhibit its metabolism. Particular caution is advised when drugs that inhibit CYP450 3A4 (e.g., azole antifungal agents, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, protease inhibitors, telithromycin) and CYP450 2C8 (e.g., gemfibrozil, clopidogrel) are used together with loperamide, or when one or more of these drugs are combined with inhibitors of P-glycoprotein transport (e.g., amiodarone, cyclosporine, diltiazem, dronedarone, quinidine, verapamil), since they may act synergistically to increase loperamide concentrations. Patients should be counseled to not exceed the recommended dosage and frequency or duration of use of loperamide, and to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. If loperamide-induced cardiotoxicity is suspected, promptly discontinue loperamide and initiate therapy to manage and prevent cardiac arrhythmias and adverse outcomes. Electrical pacing or cardioversion may be necessary if torsade de pointes persists despite pharmacotherapy.

References
1	Eggleston W, Clark KH, Marraffa JM "Loperamide abuse associated with cardiac dysrhythmia and death." Ann Emerg Med 69 (2017): 83-6. [PMID: 27140747]
2	Kim KA, Chung J, Jung DH, Park JY "Identification of cytochrome P450 isoforms involved in the metabolism of loperamide in human liver microsomes." Eur J Clin Pharmacol 60 (2004): 575-81. [PMID: 15365656]
3	Niemi M, Tornio A, Pasanen MK, Fredrikson H, Neuvonen PJ, Backman JT "Itraconazole, gemfibrozil and their combination markedly raise the plasma concentrations of loperamide." Eur J Clin Pharmacol 62 (2006): 463-72. [PMID: 16758263]
4	Product Information. Imodium (loperamide). Janssen Pharmaceutica, Titusville, NJ.
5	Tayrouz Y, Ganssmann B, Ding R, et al. "Ritonavir increases loperamide plasma concentrations without evidence for P-glycoprotein involvement." Clin Pharmacol Ther 70 (2001): 405-14. [PMID: 11719726]
6	US Food and Drug Administration "FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse.".