Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIFVAW78U)
Drug Name			Tacrolimus		Drug Info		Fosamprenavir		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Immunosuppressive Agents				Anti-Hiv Agents
Structure

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

Drug Name		Tacrolimus				Fosamprenavir
Mechanism		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 Fosamprenavir mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised when tacrolimus is used with protease inhibitors (PIs). Dosage reduction and/or prolongation of the dosing interval for tacrolimus will likely be required. Tacrolimus blood levels and renal function should be checked frequently and the dosage adjusted accordingly, particularly following initiation or discontinuation of PI therapy. 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
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3	Jain AB, Venkataramanan R, Eghtesad B, et al. "Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients." Liver Transpl 9 (2003): 954-60. [PMID: 12942457]
4	Jain AK, Venkataramanan R, Shapiro R, et al. "Interaction between tacrolimus and antiretroviral agents in human immunodeficiency virus-positive liver and kidney transplantation patients." Transplant Proc 34 (2002): 1540-1. [PMID: 12176474]
5	Jain AK, Venkataramanan R, Shapiro R, et al. "The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients." Liver Transpl 8 (2002): 841-5. [PMID: 12200788]
6	Mertz D, Battegay M, Marzolini C, Mayr M "Drug-Drug Interaction in a Kidney Transplant Recipient Receiving HIV Salvage Therapy and Tacrolimus." Am J Kidney Dis (2009):. [PMID: 19346040]
7	Pea F, Tavio M, Pavan F, et al. "Drop in trough blood concentrations of tacrolimus after switching from nelfinavir to fosamprenavir in four HIV-infected liver transplant patients." Antivir Ther 13 (2008): 739-42. [PMID: 18771060]
8	Product Information. Agenerase (amprenavir). Glaxo Wellcome, Research Triangle Pk, NC.
9	Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
10	Product Information. Fortovase (saquinavir) Roche Laboratories, Nutley, NJ.
11	Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
12	Product Information. Norvir (ritonavir). Abbott Pharmaceutical, Abbott Park, IL.
13	Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
14	Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
15	Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
16	Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.
17	Schonder KS, Shullo MA, Okusanya O "Tacrolimus and lopinavir/ritonavir interaction in liver transplantation." Ann Pharmacother 37 (2003): 1793-6. [PMID: 14632538]
18	Tsapepas DS, Webber AB, Aull MJ, Figueiro JM, Saal SD "Managing the atazanavir-tacrolimus drug interaction in a renal transplant recipient." Am J Health Syst Pharm 68 (2011): 138-42. [PMID: 21200061]
19	Teicher E, Vincent I, Bonhomme-Faivre L, et al. "Effect of Highly Active Antiretroviral Therapy on Tacrolimus Pharmacokinetics in Hepatitis C Virus and HIV Co-Infected Liver Transplant Recipients in the ANRS HC-08 Study." Clin Pharmacokinet 46 (2007): 941-52. [PMID: 17922559]