Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIOVBX8TS)
Drug Name			Dofetilide		Drug Info		Cimetidine		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiarrhythmic Agents				Antiulcer Agents
Structure

Mechanism of Dofetilide-Cimetidine Interaction (Severity Level: Major)
Transporter inhibition Click to Show/Hide Mechanism Graph

Drug Name		Dofetilide				Cimetidine
Mechanism		OCT2 substrate				OCT2 inhibitor
Key Mechanism Factor 1
		Factor Name		Solute carrier family 22 member 2				× Structure Sequence MPTTVDDVLEHGGEFHFFQKQMFFLLALLSATFAPIYVGIVFLGFTPDHRCRSPGVAELSLRCGWSPAEELNYTVPGPGPAGEASPRQCRRYEVDWNQSTFDCVDPLASLDTNRSRLPLGPCRDGWVYETPGSSIVTEFNLVCANSWMLDLFQSSVNVGFFIGSMSIGYIADRFGRKLCLLTTVLINAAAGVLMAISPTYTWMLIFRLIQGLVSKAGWLIGYILITEFVGRRYRRTVGIFYQVAYTVGLLVLAGVAYALPHWRWLQFTVSLPNFFFLLYYWCIPESPRWLISQNKNAEAMRIIKHIAKKNGKSLPASLQRLRLEEETGKKLNPSFLDLVRTPQIRKHTMILMYNWFTSSVLYQGLIMHMGLAGDNIYLDFFYSALVEFPAAFMIILTIDRIGRRYPWAASNMVAGAACLASVFIPGDLQWLKIIISCLGRMGITMAYEIVCLVNAELYPTFIRNLGVHICSSMCDIGGIITPFLVYRLTNIWLELPLMVFGVLGLVAGGLVLLLPETKGKALPETIEEAENMQRPRKNKEKMIYLQVQKLDIPLN
		Gene Name		44836
		Uniprot ID		S22A2_HUMAN
		KEGG Pathway		hsa:6582
		Protein Family		Major facilitator (TC 2.A.1) superfamily
		Protein Function		Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamine, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity. Click to Show/Hide
Mechanism Description		Decreased clearance of Dofetilide due to the transporter inhibition by Cimetidine

Recommended Action
Management		Given the risk of concentration-dependent QT prolongation, concomitant use of dofetilide with OCT-2 inhibitors is considered contraindicated.

References
1	Product Information. Tikosyn (dofetilide) Pfizer US Pharmaceuticals, Atlanta, GA.
2	Abel S, Nichols DJ, Brearley CJ, Eve MD "Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide." Br J Clin Pharmacol 49 (2000): 64-71.[PMID: 10606839]
3	Johnson BF, Cheng SL, Venitz J "Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic." J Clin Pharmacol 41 (2001): 1248-56.[PMID: 11697758]