Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4I9SUNQ)
Drug Name			Nitisinone		Drug Info		Doxepin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antineoplastics				Antidepressants
Structure

Mechanism of Nitisinone-Doxepin Interaction (Severity Level: Moderate)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Nitisinone				Doxepin
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 Doxepin caused by Nitisinone mediated inhibition of CYP450 enzyme

Recommended Action
Management		If nitisinone is used concomitantly with sensitive CYP450 2C9 substrates (e.g., celecoxib, tolbutamide) or CYP450 2C9 substrates with a narrow therapeutic index (e.g., phenytoin, warfarin), the dosage of the drug metabolized by CYP450 2C9 should be reduced by one-half and additional dosage adjustments made as needed to maintain therapeutic drug concentrations. Clinical and laboratory monitoring should be considered whenever nitisinone is added to or withdrawn from therapy with CYP450 2C9 substrates. Refer to individual substrate prescribing information for additional dosing recommendations.

References
1	Canadian Pharmacists Association.
2	Cerner Multum, Inc. "Australian Product Information.".
3	Product Information. Orfadin (nitisinone). Orphan Pharmaceuticals USA, Inc, Nashville, TN.