Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIKNDPS30)
Drug Name			Mexiletine		Drug Info		Paroxetine		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiarrhythmic Agents				Antidepressants
Structure

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

Drug Name		Mexiletine				Paroxetine
Mechanism		CYP450 2D6 substrate				CYP450 2D6 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2D6				× Structure Sequence MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQLRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVFLARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDKAVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKVLRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVADLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVIHEVQRFGDIVPLGVTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHFLDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGVFAFLVSPSPYELCAVPR
		Gene Name		CYP2D6
		Uniprot ID		CP2D6_HUMAN
		KEGG Pathway		hsa:1565
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of fatty acids, steroids and retinoids (PubMed:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, 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:18698000, PubMed:19965576, PubMed:20972997, PubMed:21289075, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:19965576, PubMed:20972997). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:18698000, PubMed:21289075). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Catalyzes the oxidative transformations of all-trans retinol to all-trans retinal, a precursor for the active form all-trans-retinoic acid (PubMed:10681376). Also involved in the oxidative metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants. Click to Show/Hide
Mechanism Description		Decreased metabolism of Mexiletine caused by Paroxetine mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised if certain SSRIs, particularly fluoxetine or paroxetine, must be used concomitantly with antiarrhythmic agents that are metabolized by CYP450 2D6. Lower initial dosages of the antiarrhythmic agent may be appropriate. Patients who are already stabilized on their antiarrhythmic regimen should be monitored for altered effects on myocardial conduction following addition or discontinuation of SSRI therapy (up to 2 weeks for most SSRIs and 5 weeks for fluoxetine due to its long half-life), and the antiarrhythmic dosage adjusted if necessary. alternatively, an antidepressant that does not interfere with 2D6 metabolism may be considered, such as citalopram, escitalopram, or venlafaxine.

References
1	Alfaro CL, Lam YWF, Simpson J, Ereshefsky L "CYP2D6 status of extensive metabolizers after multiple-dose fluoxetine, fluvoxamine, paroxetine, or sertraline." J Clin Psychopharmacol 19 (1999): 155-63. [PMID: 10211917]
2	Cai WM, Chen B, Zhou Y, Zhang YD "Fluoxetine impairs the CYP2D6-mediated metabolism of propafenone enantiomers in healthy Chinese volunteers." Clin Pharmacol Ther 66 (1999): 516-21. [PMID: 10579479]
3	Hemeryck A, DeVriendt C, Belpaire FM "Effect of selective serotonin reuptake inhibitors on the oxidative metabolism of propafenone: In vitro studies using human liver microsomes." J Clin Psychopharmacol 20 (2000): 428-34. [PMID: 10917404]
4	Kusumoto M, Ueno K, Oda A, Takeda K, Mashimo K, Takaya K, Fujimura Y, Nishihori T, Tanaka K "Effect of fluvoxamine on the pharmacokinetics of mexiletine in healthy Japanese men." Clin Pharmacol Ther 69 (2001): 104-7. [PMID: 11240973]
5	Product Information. Paxil (paroxetine). GlaxoSmithKline, Research Triangle Park, NC.
6	Product Information. Prozac (fluoxetine). Dista Products Company, Indianapolis, IN.
7	Product Information. Zoloft (sertraline). Roerig Division, New York, NY.