Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI5LD897P)
Drug Name			Mexiletine		Drug Info		Oxtriphylline		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiarrhythmic Agents				Bronchodilators
Structure

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

Drug Name		Mexiletine				Oxtriphylline
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 Oxtriphylline caused by Mexiletine mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised when theophylline is used with mexiletine. Close monitoring of serum theophylline levels is recommended, particularly following the addition, discontinuation or change of dosage of mexiletine, and the theophylline dosage adjusted accordingly. Patients should be advised to notify their physician if they experience signs of theophylline toxicity such as nausea, vomiting, diarrhea, headache, restlessness, insomnia, seizures, palpitations, and cardiac arrhythmia.

References
1	Hurwitz A, Vacek JL, Botteron GW, et al "Mexiletine effects on theophylline disposition." Clin Pharmacol Ther 50 (1991): 299-307. [PMID: 1914365]
2	Katz A, Buskila D, Sukenik S "Oral mexiletine-theophylline interaction." Int J Cardiol 17 (1987): 227-8. [PMID: 3679607]
3	Kessler KM, Interian A, Cox M, et al "Proarrhythmia related to a kinetic and dynamic interaction of mexiletine and theophylline." Am Heart J 117 (1989): 964-6. [PMID: 2929410]
4	Loi CM, Wei X, Vestal RE "Inhibition of theophylline metabolism by mexiletine in young male and female nonsmokers." Clin Pharmacol Ther 49 (1991): 571-80. [PMID: 2029830]
5	Stanley R, Comer T, Taylor JL, Saliba D "Mexiletine-theophylline interaction." Am J Med 86 (1989): 733-4. [PMID: 2729333]
6	Stoysich AM, Mohiuddin SM, Destache CJ, et al "Influence of mexiletine on the pharmacokinetics of theophylline in healthy volunteers." J Clin Pharmacol 31 (1991): 354-7. [PMID: 2037708]
7	Ueno K, Miyai K, Kato M, et al "Mechanism of interaction between theophylline and mexiletine." DICP 25 (1991): 727-30. [PMID: 1949927]
8	Ueno K, Miyai K, Seki T, Kawaguchi Y "Interaction between theophylline and mexiletine." DICP 24 (1990): 471-2. [PMID: 1693023]
9	Upton RA "Pharmacokinetic interactions between theophylline and other medication (Part II)." Clin Pharmacokinet 20 (1991): 135-50. [PMID: 1709398]