Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIJ8CYUIB)
Drug Name			Fluvoxamine		Drug Info		Theophylline		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antidepressants				Bronchodilators
Structure

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

Drug Name		Fluvoxamine				Theophylline
Mechanism		CYP450 1A2 inhibitor				CYP450 1A2 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 1A2				× Structure Sequence MALSQSVPFSATELLLASAIFCLVFWVLKGLRPRVPKGLKSPPEPWGWPLLGHVLTLGKNPHLALSRMSQRYGDVLQIRIGSTPVLVLSRLDTIRQALVRQGDDFKGRPDLYTSTLITDGQSLTFSTDSGPVWAARRRLAQNALNTFSIASDPASSSSCYLEEHVSKEAKALISRLQELMAGPGHFDPYNQVVVSVANVIGAMCFGQHFPESSDEMLSLVKNTHEFVETASSGNPLDFFPILRYLPNPALQRFKAFNQRFLWFLQKTVQEHYQDFDKNSVRDITGALFKHSKKGPRASGNLIPQEKIVNLVNDIFGAGFDTVTTAISWSLMYLVTKPEIQRKIQKELDTVIGRERRPRLSDRPQLPYLEAFILETFRHSSFLPFTIPHSTTRDTTLNGFYIPKKCCVFVNQWQVNHDPELWEDPSEFRPERFLTADGTAINKPLSEKMMLFGMGKRRCIGEVLAKWEIFLFLAILLQQLEFSVPPGVKVDLTPIYGLTMKHARCEHVQARLRFSIN
		Gene Name		CYP1A2
		Uniprot ID		CP1A2_HUMAN
		KEGG Pathway		hsa:1544
		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:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, 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:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable). Click to Show/Hide
Mechanism Description		Decreased metabolism of Theophylline caused by Fluvoxamine mediated inhibition of CYP450 enzyme

Recommended Action
Management		The use of theophylline or its salts in combination with fluvoxamine should generally be avoided. If coadministration is required, a reduction of theophylline dosage by one-half to two-thirds should be considered. Pharmacologic response and serum levels should be closely monitored following initiation, discontinuation or change of dosage of fluvoxamine, and the theophylline dosage adjusted accordingly. Patients should be advised to contact their physician if they experience signs and symptoms suggestive of theophylline toxicity such as nausea, vomiting, diarrhea, anorexia, headache, tremor, irritability, confusion, insomnia, seizure, palpitation, and arrhythmia. Other selective serotonin reuptake inhibitors including citalopram, escitalopram, fluoxetine, paroxetine, and sertraline do not significantly inhibit CYP450 1A2 and may be safer alternatives in theophylline-treated patients.

References
1	Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S "Fluvoxamine is a potent inhibitor of cytochrome P4501A2." Biochem Pharmacol 45 (1993): 1211-4. [PMID: 8466541]
2	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3	Devane CL, Markowitz JS, Hardesty SJ, Mundy S, Gill HS "Fluvoxamine-induced theophylline toxicity." Am J Psychiatry 154 (1997): 1317-8. [PMID: 9286199]
4	Hardman JG, Gilman AG, Limbird LE eds. "Goodman and Gilman's the Pharmacological Basis of Therapeutics. 9th ed." New York, NY: McGraw-Hill (1995):.
5	Nemeroff CB, Devane CL, Pollock BG "Newer antidepressants and the cytochrome p450 system." Am J Psychiatry 153 (1996): 311-20. [PMID: 8610817]
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7	Product Information. Luvox (fluvoxamine). Solvay Pharmaceuticals Inc, Marietta, GA.
8	Rasmussen BB, Jeppesen U, Gaist D, Brosen K "Griseofulvin and fluvoxamine interactions with the metabolism of theophylline." Ther Drug Monit 19 (1997): 56-62. [PMID: 9029748]
9	Rasmussen BB, Maenpaa J, Pelkonen O, et al "Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine." Br J Clin Pharmacol 39 (1995): 151-9. [PMID: 7742153]
10	Sperber AD "Toxic interaction between fluvoxamine and sustained release theophylline in an 11-year-old boy." Drug Saf 6 (1991): 460-2. [PMID: 1793525]
11	van den Brekel AM, Harriington L "Toxic effects of theophylline caused by fluoxamine." CMAJ 151 (1994): 1289-90. [PMID: 7954177]
12	Yao C, Kunze KL, Kharasch ED, et al. "Fluvoxamine-theophylline interaction: Gap between in vitro and in vivo inhibition constants toward cytochrome P4501A2." Clin Pharmacol Ther 70 (2001): 415-24. [PMID: 11719727]