Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIHUSG1TD)
Drug Name			Gemfibrozil		Drug Info		Siponimod		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antihyperammonia Agents				Selective Immunosuppressants
Structure

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

Drug Name		Gemfibrozil				Siponimod
Mechanism		CYP450 2C9 inhibitor				CYP450 2C9 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2C9				× Structure Sequence MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICSIIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFMKSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTETTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYIDLLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFKKSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVPPFYQLCFIPV
		Gene Name		CYP2C9
		Uniprot ID		CP2C9_HUMAN
		KEGG Pathway		hsa:1559
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). 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:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:7574697, PubMed:15766564, PubMed:19965576, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9866708, PubMed:9435160). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031). Click to Show/Hide
Mechanism Description		Decreased metabolism of Siponimod caused by Gemfibrozil mediated inhibition of CYP450 enzyme

Recommended Action
Management		Concomitant use of siponimod with a moderate or strong CYP450 2C9/3A4 dual inhibitor (e.g., fluconazole, mifepristone) or a moderate CYP450 2C9 inhibitor (e.g., abiraterone, amiodarone, fenofibrate, gemfibrozil, nitisinone, oxandrolone) in combination with a moderate or strong CYP450 3A4 inhibitor (e.g., amprenavir, aprepitant, atazanavir, boceprevir, ceritinib, chloramphenicol, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, dalfopristin-quinupristin, darunavir, delavirdine, diltiazem, dronedarone, erythromycin, fedratinib, fluvoxamine, fosamprenavir, fosaprepitant, fosnetupitant, fusidic acid, idelalisib, imatinib, indinavir, isavuconazole, itraconazole, ketoconazole, letermovir, mibefradil, nefazodone, nelfinavir, netupitant, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, troleandomycin, verapamil, voriconazole, voxelotor) is not recommended. Caution is advised if siponimod is used in combination with moderate CYP450 2C9 inhibitors.

References
1	Cerner Multum, Inc. "Australian Product Information.".
2	Product Information. Mayzent (siponimod). Novartis Pharmaceuticals, East Hanover, NJ.