Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIV9A541S)
  Drug Name Tacrolimus Drug Info Troleandomycin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Immunosuppressive Agents Antibiotics
  Structure

 Mechanism of Tacrolimus-Troleandomycin Interaction (Severity Level: Major)
     Transporter inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Tacrolimus Troleandomycin
      Mechanism 1 P-gp substrate P-gp inhibitor
      Key Mechanism Factor 1
Factor Name P-glycoprotein 1
×
Structure Sequence
MDLEGDRNGGAKKKNFFKLNNKSEKDKKEKKPTVSVFSMFRYSNWLDKLYMVVGTLAAIIHGAGLPLMMLVFGEMTDIFANAGNLEDLMSNITNRSDINDTGFFMNLEEDMTRYAYYYSGIGAGVLVAAYIQVSFWCLAAGRQIHKIRKQFFHAIMRQEIGWFDVHDVGELNTRLTDDVSKINEGIGDKIGMFFQSMATFFTGFIVGFTRGWKLTLVILAISPVLGLSAAVWAKILSSFTDKELLAYAKAGAVAEEVLAAIRTVIAFGGQKKELERYNKNLEEAKRIGIKKAITANISIGAAFLLIYASYALAFWYGTTLVLSGEYSIGQVLTVFFSVLIGAFSVGQASPSIEAFANARGAAYEIFKIIDNKPSIDSYSKSGHKPDNIKGNLEFRNVHFSYPSRKEVKILKGLNLKVQSGQTVALVGNSGCGKSTTVQLMQRLYDPTEGMVSVDGQDIRTINVRFLREIIGVVSQEPVLFATTIAENIRYGRENVTMDEIEKAVKEANAYDFIMKLPHKFDTLVGERGAQLSGGQKQRIAIARALVRNPKILLLDEATSALDTESEAVVQVALDKARKGRTTIVIAHRLSTVRNADVIAGFDDGVIVEKGNHDELMKEKGIYFKLVTMQTAGNEVELENAADESKSEIDALEMSSNDSRSSLIRKRSTRRSVRGSQAQDRKLSTKEALDESIPPVSFWRIMKLNLTEWPYFVVGVFCAIINGGLQPAFAIIFSKIIGVFTRIDDPETKRQNSNLFSLLFLALGIISFITFFLQGFTFGKAGEILTKRLRYMVFRSMLRQDVSWFDDPKNTTGALTTRLANDAAQVKGAIGSRLAVITQNIANLGTGIIISFIYGWQLTLLLLAIVPIIAIAGVVEMKMLSGQALKDKKELEGSGKIATEAIENFRTVVSLTQEQKFEHMYAQSLQVPYRNSLRKAHIFGITFSFTQAMMYFSYAGCFRFGAYLVAHKLMSFEDVLLVFSAVVFGAMAVGQVSSFAPDYAKAKISAAHIIMIIEKTPLIDSYSTEGLMPNTLEGNVTFGEVVFNYPTRPDIPVLQGLSLEVKKGQTLALVGSSGCGKSTVVQLLERFYDPLAGKVLLDGKEIKRLNVQWLRAHLGIVSQEPILFDCSIAENIAYGDNSRVVSQEEIVRAAKEANIHAFIESLPNKYSTKVGDKGTQLSGGQKQRIAIARALVRQPHILLLDEATSALDTESEKVVQEALDKAREGRTCIVIAHRLSTIQNADLIVVFQNGRVKEHGTHQQLLAQKGIYFSMVSVQAGTKRQ
Gene Name ABCB1
Uniprot ID MDR1_HUMAN
KEGG Pathway hsa:5243
Protein Family ABC transporter superfamily
Protein Function
Translocates drugs and phospholipids across the membrane (PubMed:8898203, PubMed:2897240, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:9038218).
    Click to Show/Hide
      Mechanism Description
  • Decreased clearance of Tacrolimus due to the transporter inhibition by Troleandomycin 
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Tacrolimus Troleandomycin
      Mechanism 2 CYP450 3A4 substrate CYP450 3A4 inhibitor
      Key Mechanism Factor 2
Factor Name Cytochrome P450 3A4
×
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 Tacrolimus 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 Tacrolimus Troleandomycin
      Mechanism 3 Prolong QT interval Prolong QT interval
      Key Mechanism Factor 3
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 Tacrolimus and Troleandomycin 

Recommended Action
      Management Caution is advised when tacrolimus is used with macrolide or ketolide antibiotics that significantly inhibit CYP450 3A4 such as clarithromycin, erythromycin, josamycin, and telithromycin. A preemptive dosage reduction for tacrolimus may be appropriate in some cases. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of macrolide antibiotic therapy, and the tacrolimus dosage adjusted accordingly. In addition, patients should be closely monitored for development of serious adverse effects such as nephrotoxicity, lymphoma and other malignancies, infections, diabetes, neurotoxicity (tremor, paraesthesia, encephalopathy, delirium, coma), hyperkalemia, QT prolongation, myocardial hypertrophy, and hypertension. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

References
1 Cakaloglu Y, Tredger JM, Devlin J, Williams R "Importance of cytochrome p-450IIIA activity in determining dosage and blood levels of FK 506 and cyclosporine in liver transplant recipients." Hepatology 20 (1994): 309-16. [PMID: 7519161]
2 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
3 Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM "Interactions between FK506 and rifampin or erythromycin in pediatric liver recipients." Transplantation 59 (1995): 1217-8. [PMID: 7537398]
4 Gomez G, Alvarez ML, Errasti P, Lavilla FJ, Garcia N, Ballester B, Garcia I, Purroy A "Acute tacrolimus nephrotoxicity in renal transplant patients treated with clarithromycin." Transplant Proc 31 (1999): 2250-1. [PMID: 10500563]
5 Homma S, Takahashi KI, Nihei S, Kato F, Sugihara S, Nunoda S "The successful management of respiratory complications with long-term, low-dose macrolide administration in pediatric heart transplant recipients." Int Heart J (2014):. [PMID: 25297501]
6 Ibrahim RB, Abella EM, Chandrasekar PH "Tacrolimus-clarithromycin interaction in a patient receiving bone marrow transplantation." Ann Pharmacother 36 (2002): 1971-1972. [PMID: 12452763]
7 Jensen C, Jordan M, Shapiro R, et al. "Interaction between tacrolimus and erythromycin." Lancet 344 (1994): 825. [PMID: 7521928]
8 Katari SR, Magnone M, Shapiro R, et al "Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients." Clin Transplant 11 (1997): 237-42. [PMID: 9193849]
9 Kunicki PK, Sobieszczanska-Malek M "Pharmacokinetic interaction between tacrolimus and clarithromycin in a heart transplant patient." Ther Drug Monit 27 (2005): 107-108. [PMID: 15665756]
10 Moreno M, Latorre A, Manzanares C, et al "Clinical management of tacrolimus drug interactions in renal transplant patients." Transplant Proc 31 (1999): 2252-3. [PMID: 10500564]
11 Parissis H, Gould K, Dark J "Dangerous drug interactions leading to hemolytic uremic syndrome following lung transplantation." J Cardiothorac Surg 5 (2010): 70. [PMID: 20813025]
12 Pea F, Furlanut M "Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions." Clin Pharmacokinet 40 (2001): 833-868. [PMID: 11735605]
13 Product Information. Biaxin (clarithromycin). Abbott Pharmaceutical, Abbott Park, IL.
14 Product Information. Ketek (telithromycin). Aventis Pharmaceuticals, Bridgewater, NJ.
15 Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
16 Shaeffer MS, Collier D, Sorrell MF "Interaction between FK506 and erythromycin." Ann Pharmacother 28 (1994): 280-1. [PMID: 7513563]
17 Wolter K, Wagner K, Philipp T, Fritschka E "Interaction between FK 506 and clarithromycin in a renal transplant patient." Eur J Clin Pharmacol 47 (1994): 207-8. [PMID: 7532134]