Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIA6UDGWK)
  Drug Name Tacrolimus Drug Info Posaconazole Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Immunosuppressive Agents Antifungal Agents
  Structure

 Mechanism of Tacrolimus-Posaconazole Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Tacrolimus Posaconazole
      Mechanism 1 CYP450 3A4 substrate CYP450 3A4 inhibitor
      Key Mechanism Factor 1
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 Posaconazole 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 Posaconazole
      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 Tacrolimus and Posaconazole 

Recommended Action
      Management Caution is advised if tacrolimus is used concomitantly with azole antifungal agents. When initiating therapy with posaconazole or voriconazole in patients already receiving tacrolimus, the manufacturers recommend that tacrolimus dosage be reduced by about two-thirds initially. No specific dosing recommendations are available for use with other azole antifungal agents, although a dosage reduction for tacrolimus should also be considered. Frequent monitoring of tacrolimus whole blood levels should be performed during and after discontinuation of azole antifungal therapy, and the tacrolimus dosage adjusted accordingly. 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 Albengres E, Le Louet H, Tillement JP "Systemic antifungal agents. Drug interactions of clinical significance." Drug Saf 18 (1998): 83-97. [PMID: 9512916]
2 Assan R, Fredj G, Larger E, Feutren G, Bismuth H "FK 506/fluconazole interaction enhances FK 506 nephrotoxicity." Diabete Metab 20 (1994): 49-52. [PMID: 7520007]
3 Billaud EM, Guillemain R, Tacco F, Chevalier P "Evidence for a pharmacokinetic interaction between itraconazole and tacrolimus in organ transplant patients." Br J Clin Pharmacol 46 (1998): 271-4. [PMID: 9764970]
4 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]
5 Capone D, Gentile A, Imperatore P, Palmiero G, Basile V "Effects of itraconazole on tacrolimus blood concentrations in a renal transplant recipient." Ann Pharmacother 33 (1999): 1124-5. [PMID: 10534229]
6 Cerner Multum, Inc. "Australian Product Information.".
7 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
8 Dodds-Ashley E "Management of drug and food interactions with azole antifungal agents in transplant recipients." Pharmacotherapy 30 (2010): 842-54. [PMID: 20653361]
9 Floren LC, Bekersky I, Benet LZ, et al. "Tacrolimus oral bioavailability doubles with coadministration of ketoconazole." Clin Pharmacol Ther 62 (1997): 41-9. [PMID: 9246018]
10 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]
11 Macias MO, Salvador P, Hurtado JL, Martin I "Tacrolimus-itraconazole interaction in a kidney transplant patient." Ann Pharmacother 34 (2000): 536. [PMID: 10772445]
12 Manez R, Martin M, Raman V, et al. "Fluconazole therapy in transplant recipients receiving FK506." Transplantation 57 (1994): 1521-3. [PMID: 7515201]
13 Mieles L, Venkataramanan R, Yokoyama I, Warty VJ, Starzl TE "Interaction between FK506 and clotrimazole in a liver transplant recipient." Transplantation 52 (1991): 1086-7. [PMID: 1721250]
14 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]
15 Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR "Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients." Transplantation 61 (1996): 1268-72. [PMID: 8610430]
16 Pai MP, Allen S "Voriconazole inhibition of tacrolimus metabolism." Clin Infect Dis 36 (2003): 1089-91. [PMID: 12684931]
17 Product Information. Noxafil (posaconazole). Schering-Plough Corporation, Kenilworth, NJ.
18 Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
19 Product Information. VFEND (voriconazole). Pfizer U.S. Pharmaceuticals, New York, NY.
20 Soltero L, Carbajal H, Rodriguez-Montalvo C, Valdes A "Coadministration of tacrolimus and ketoconazole in renal transplant recipients: cost analysis and review of metabolic effects." Transplant Proc 35 (2003): 1319-21. [PMID: 12826147]
21 Vasquez EM, Pollak R, Benedetti E "Clotrimazole increases tacrolimus blood levels: a drug interaction in kidney transplant patients." Clin Transplant 15 (2001): 95-9. [PMID: 11264634]
22 Venkatakrishnan K, von Moltke LL, Greenblatt DJ "Effects of the antifungal agents on oxidative drug metabolism: clinical relevance." Clin Pharmacokinet 38 (2000): 111-80. [PMID: 10709776]
23 Venkataramanan R, Zang S, Gayowski T, Singh N "Voriconazole inhibition of the metabolism of tacrolimus in a liver transplant recipient and in human liver microsomes." Antimicrob Agents Chemother 46 (2002): 3091-3. [PMID: 12183280]