Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI4RZ0YIS)
Drug Name			Trazodone		Drug Info		Conivaptan		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antidepressants				Vasopressin Antagonists
Structure

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

Drug Name		Trazodone				Conivaptan
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		Gene Name		CYP3A4
		Uniprot ID		CP3A4_HUMAN
		KEGG Pathway		hsa:1576
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, 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). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981). Click to Show/Hide
Mechanism Description		Decreased metabolism of Trazodone caused by Conivaptan mediated inhibition of CYP450 enzyme

Recommended Action
Management		If concomitant use cannot be avoided, a lower dosage of trazodone should be considered during coadministration with a potent CYP450 3A4 inhibitor. Pharmacologic response to trazodone should be monitored more closely whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy, and the trazodone dosage adjusted as necessary. Patients should seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.

References
1	Dattilo PB, Nordin C "Prolonged QT associated with an overdose of trazodone." J Clin Psychiatry 68 (2007): 1309-10. [PMID: 17854263]
2	Goodnick PJ, Jerry J, Parra F "Psychotropic drugs and the ECG: focus on the QTc interval." Expert Opin Pharmacother 3 (2002): 479-98. [PMID: 11996627]
3	Greenblatt DJ, von Moltke LL, Harmatz JS, et al. "Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone." J Clin Pharmacol 43 (2003): 414-22. [PMID: 12723462]
4	Levenson JL "Prolonged QT interval after trazodone overdose." Am J Psychiatry 156 (1999): 969-70. [PMID: 10360146]
5	Mazur A, Strasberg B, Kusniec J, Sclarovsky S "QT prolongation and polymorphous ventricular tachycardia associated with trasodone-amiodarone combination." Int J Cardiol 52 (1995): 27-9. [PMID: 8707432]
6	Product Information. Agenerase (amprenavir). Glaxo Wellcome, Research Triangle Pk, NC.
7	Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
8	Product Information. Desyrel (trazodone). Bristol-Myers Squibb, Princeton, NJ.
9	Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
10	Product Information. Norvir (ritonavir). Abbott Pharmaceutical, Abbott Park, IL.
11	Product Information. Oleptro (traZODone). Labopharm Inc, Laval, AL.
12	Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
13	Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
14	Product Information. Stribild (cobicistat/elvitegravir/emtricitabine/tenofov). Gilead Sciences, Foster City, CA.
15	Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.