Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIT4X6L5K)
Drug Name			Tinidazole		Drug Info		Anisindione		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Amebicides/Antibiotics				Anticoagulants
Structure

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

Drug Name		Tinidazole				Anisindione
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 Anisindione caused by Tinidazole mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given its structural similarities to metronidazole, the potential for interaction with warfarin and other oral anticoagulants should be considered during coadministration with tinidazole. The INR should be checked frequently and anticoagulant dosage adjusted accordingly, particularly following initiation and for up to 8 days after discontinuation of tinidazole therapy in patients who are stabilized on their anticoagulant regimen. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

References
1	Dean RP, Talbert RL "Bleeding associated with concurrent warfarin and metronidazole therapy." Drug Intell Clin Pharm 14 (1980): 864-6.
2	Hermans JJ, Thijssen HH "Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics." Br J Pharmacol 110 (1993): 482-90. [PMID: 8220911]
3	Kazmier FJ "A significant interaction between metronidazole and warfarin." Mayo Clin Proc 51 (1976): 782-4. [PMID: 994556]
4	Kelly JG, O'Malley K "Clinical pharmacokinetics of oral anticoagulants." Clin Pharmacokinet 4 (1979): 1-15. [PMID: 369763]
5	Miners JO, Birkett DJ "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism." Br J Clin Pharmacol 45 (1998): 525-38. [PMID: 9663807]
6	O'Reilly RA "The stereoselective interaction of warfarin and metronidazole in man." N Engl J Med 295 (1976): 354-7. [PMID: 934223]
7	Product Information. Tindamax (tinidazole). Presutti Laboratories Inc, Arlington Heights, IL.
8	Serlin MJ, Breckenridge AM "Drug interactions with warfarin." Drugs 25 (1983): 610-20. [PMID: 6347619]
9	Thijssen HH, Flinois JP, Beaune PH "Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes." Drug Metab Disposition 28 (2000): 1284-90. [PMID: 11038154]
10	Wells PS, Holbrook AM, Crowther NR, Hirsh J "Interactions of warfarin with drugs and food." Ann Intern Med 121 (1994): 676-83. [PMID: 7944078]
11	Laine K, Forsstrom J, Gronroos P, Irjala K, Kailajarvi M, Scheinin M "Frequency and clinical outcome of potentially harmful drug metabolic interactions in patients hospitalized on internal and pulmonary medicine wards: Focus on warfarin and cisapride." Ther Drug Monit 22 (2000): 503-9. [PMID: 11034253]