Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIB8Y1CJ9)
  Drug Name Disopyramide Drug Info Troleandomycin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiarrhythmic Agents Antibiotics
  Structure

 Mechanism of Disopyramide-Troleandomycin Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Disopyramide Troleandomycin
      Mechanism 1 CYP450 3A4 substrate CYP450 3A4 inhibitor
      Key Mechanism Factor 1
Factor Name Cytochrome P450 3A4
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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 Disopyramide caused by Troleandomycin mediated inhibition of CYP450 enzyme
     Increased risk of prolong QT interval Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Disopyramide Troleandomycin
      Mechanism 2 Prolong QT interval Prolong QT interval
      Key Mechanism Factor 2
Factor Name QT interval
Factor Description Long QT syndrome is a heart signaling disorder that can cause a fast, chaotic heartbeat (arrhythmia). Many people may not exhibit symptoms, and usually the condition is detected during routine medical tests. In others, the most common symptoms include: sudden fainting, palpitations, dizziness, seizures, sudden death.
      Mechanism Description
  • Increased risk of prolong QT interval by the combination of Disopyramide and Troleandomycin 

Recommended Action
      Management The concurrent use of disopyramide with other medications that can prolong the QT interval should generally be avoided unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together, especially to patients with underlying risk factors. Patients should be advised to seek 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 Cerner Multum, Inc. "Australian Product Information.".
2 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3 Choudhury L, Grais IM, Passman RS "Torsades de pointes due to drug interaction between disopyramide and clarithromycin." Heart Dis 1 (1999): 206-7. [PMID: 11720625]
4 Echizen H, Kawasaki H, Chiba K, Tani M, Ishizaki T "A potent inhibitory effect of erythromycin and other macrolide antibiotics on the mono-n-dealkylation metabolism of disopyramide with human liver microsomes." J Pharmacol Exp Ther 264 (1993): 1425-31. [PMID: 8450476]
5 Gitler B, Berger LS, Buffa SD "Torsades de pointes induced by erythromycin." Chest 105 (1994): 368-72. [PMID: 8306730]
6 Hayashi Y, Ikeda U, Hashimoto T, Watanabe T, Mitsuhashi T, Shimada K "Torsades de pointes ventricular tachycardia induced by clarithromycin and disopyramide in the presence of hypokalemia." Pacing Clin Electrophysiol 22(4 Pt 1) (1999): 672-4. [PMID: 10234723]
7 Iida H, Morita T, Suzuki E, Iwasawa K, Toyooka T, Nakajima T "Hypoglycemia induced by interaction between clarithromycin and disopyramide." Jpn Heart J 40 (1999): 91-6. [PMID: 10370402]
8 Lee KL, Jim MH, Tang SC, Tai YT "QT prolongation and torsades de pointes associated with clarithromycin." Am J Med 104 (1998): 395-6. [PMID: 9576415]
9 Paar D, Terjung B, Sauerbruch T "Life-threatening interaction between clarithromycin and disopyramide." Lancet 349 (1997): 326-7. [PMID: 9024381]
10 Product Information. Biaxin (clarithromycin). Abbott Pharmaceutical, Abbott Park, IL.
11 Product Information. Erythrocin Lactobionate (erythromycin). Abbott Pharmaceutical, Abbott Park, IL.
12 Product Information. Zithromax (azithromycin). Pfizer US Pharmaceuticals, New York, NY.
13 Ragosta M, Weihl AC, Rosenfeld LE "Potentially fatal interaction between erythromycin and disopyramide." Am J Med 86 (1989): 465-6. [PMID: 2467560]