Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI6W2EF15)
  Drug Name Cyclosporine Drug Info Simvastatin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiviral Agents Statins/Antihyperlipidemic Agents
  Structure

 Mechanism of Cyclosporine-Simvastatin Interaction (Severity Level: Major)
     Transporter inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cyclosporine Simvastatin
      Mechanism 1 OATP1B1 inhibitor OATP1B1 substrate
      Key Mechanism Factor 1
Factor Name Liver organic anion transporter 1
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Structure Sequence
MDQNQHLNKTAEAQPSENKKTRYCNGLKMFLAALSLSFIAKTLGAIIMKSSIIHIERRFEISSSLVGFIDGSFEIGNLLVIVFVSYFGSKLHRPKLIGIGCFIMGIGGVLTALPHFFMGYYRYSKETNINSSENSTSTLSTCLINQILSLNRASPEIVGKGCLKESGSYMWIYVFMGNMLRGIGETPIVPLGLSYIDDFAKEGHSSLYLGILNAIAMIGPIIGFTLGSLFSKMYVDIGYVDLSTIRITPTDSRWVGAWWLNFLVSGLFSIISSIPFFFLPQTPNKPQKERKASLSLHVLETNDEKDQTANLTNQGKNITKNVTGFFQSFKSILTNPLYVMFVLLTLLQVSSYIGAFTYVFKYVEQQYGQPSSKANILLGVITIPIFASGMFLGGYIIKKFKLNTVGIAKFSCFTAVMSLSFYLLYFFILCENKSVAGLTMTYDGNNPVTSHRDVPLSYCNSDCNCDESQWEPVCGNNGITYISPCLAGCKSSSGNKKPIVFYNCSCLEVTGLQNRNYSAHLGECPRDDACTRKFYFFVAIQVLNLFFSALGGTSHVMLIVKIVQPELKSLALGFHSMVIRALGGILAPIYFGALIDTTCIKWSTNNCGTRGSCRTYNSTSFSRVYLGLSSMLRVSSLVLYIILIYAMKKKYQEKDINASENGSVMDEANLESLNKNKHFVPSAGADSETHC
Gene Name OATP1B1
Uniprot ID SO1B1_HUMAN
KEGG Pathway hsa:10599
Protein Family Organo anion transporter (TC 2.A.60) family
Protein Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. Involved in the clearance of bile acids and organic anions from the liver.
    Click to Show/Hide
      Mechanism Description
  • Decreased clearance of Simvastatin due to the transporter inhibition by Cyclosporine 
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cyclosporine Simvastatin
      Mechanism 2 CYP450 3A4 inhibitor CYP450 3A4 substrate
      Key Mechanism Factor 2
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 Simvastatin caused by Cyclosporine mediated inhibition of CYP450 enzyme

Recommended Action
      Management Concomitant use of simvastatin and cyclosporine is considered contraindicated by the manufacturer of simvastatin. Fluvastatin or pravastatin may be considered as alternatives in patients receiving cyclosporine as they are not extensively metabolized by CYP450 3A4. However, the benefits of the use of these medicines in combination with cyclosporine should be carefully weighed against the potential risks. Statin therapy should be initiated at a lower dosage and titrated with caution.All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise, and/or dark-colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

References
1 Arnadottir M, Eriksson LO, Thysell H, Karkas JD "Plasma concentration profiles of simvastatin 3-hydroxy- 3-methylglutaryl-coenzyme A reductase inhibitory activity in kidney transplant recipients with and without ciclosporin." Nephron 65 (1993): 410-3. [PMID: 8289991]
2 Campana C, Iacona I, Regassi MB, et al. "Efficacy and pharmacokinetics of simvastatin in heart transplant recipients." Ann Pharmacother 29 (1995): 235-9. [PMID: 7606066]
3 Capone D, Stanziale P, Gentile A, Imperatore P, Pellegrino T, Basile V "Effects of simvastatin and pravastatin on hyperlipidemia and cyclosporin blood levels in renal transplant recipients." Am J Nephrol 19 (1999): 411-5. [PMID: 10393380]
4 Cerner Multum, Inc. "Australian Product Information.".
5 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
6 Corpier CL, Jones PH, Suki WN, et al. "Rhabdomyolysis and renal injury with lovastatin use. Report of two cases in cardiac transplant recipients." JAMA 260 (1988): 239-41. [PMID: 3290520]
7 East C, Alivizatos PA, Grundy SM, Jones PH, Farmer JA "Rhabdomyolysis in patients receiving lovastatin after cardiac transplantation." N Engl J Med 318 (1988): 47-8. [PMID: 3275892]
8 Francis L, Bonilla E, Soforo E, et al. "Fatal toxic myopathy attributed to propofol, methylprednisolone, and cyclosporine after prior exposure to colchicine and simvastatin." Clin Rheumatol 27 (2008): 129-31. [PMID: 17628739]
9 Gruer PJK, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA "Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin." Am J Cardiol 84 (1999): 811-5. [PMID: 10513779]
10 Gullestad L, Nordal KP, Berg KJ, Cheng H, Schwartz MS, Simonsen S "Interaction between lovastatin and cyclosporine A after heart and kidney transplantation." Transplant Proc 31 (1999): 2163-5. [PMID: 10456002]
11 Holtzman CW, Wiggins BS, Spinler SA "Role of P-glycoprotein in statin drug interactions." Pharmacotherapy 26 (2006): 1601-7. [PMID: 17064205]
12 Jardine A, Holdaas H "Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience." J Clin Pharm Ther 24 (1999): 397-408. [PMID: 10651972]
13 Kalliokoski A, Niemi M "Impact of OATP transporters on pharmacokinetics." Br J Pharmacol 158 (2009): 693-705. [PMID: 19785645]
14 Kusus M, Stapleton DD, Lertora JJL, Simon EE, Dreisbach AW "Rhabdomyolysis and acute renal failure in a cardiac transplant recipient due to multiple drug interactions." Am J Med Sci 320 (2000): 394-7. [PMID: 11149552]
15 Maltz HC, Balog DL, Cheigh JS "Rhabdomyolysis associated with concomitant use of atorvastatin and cyclosporine." Ann Pharmacother 33 (1999): 1176-9. [PMID: 10573315]
16 Najafian B, Franklin DB, Fogo AB "Acute renal failure and myalgia in a transplant patient." J Am Soc Nephrol 18 (2007): 2870-4. [PMID: 17942960]
17 Neuvonen PJ, Backman JT, Niemi M "Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin." Clin Pharmacokinet 47 (2008): 463-74. [PMID: 18563955]
18 Norman DJ, Illingworth DR, Munson J, Hosenpud J "Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin." N Engl J Med 318 (1988): 46-7. [PMID: 3275891]
19 Paoletti R, Corsini A, Bellosta S "Pharmacological interactions of statins." Atheroscler Suppl 3 (2002): 35-40. [PMID: 12044584]
20 Product Information. Lescol (fluvastatin). Novartis Pharmaceuticals, East Hanover, NJ.
21 Product Information. Mevacor (lovastatin). Merck & Co, Inc, West Point, PA.
22 Product Information. Pravachol (pravastatin). Bristol-Myers Squibb, Princeton, NJ.
23 Product Information. Zocor (simvastatin). Merck & Co, Inc, West Point, PA.
24 Rifkin SI "Multiple drug interactions in a renal transplant patient leading to simvastatin-induced rhabdomyolysis: a case report." Medscape J Med 10 (2008): 264. [PMID: 19099014]
25 Rodriguez JA, CrespoLeiro MG, Paniagua MJ, Cuenca JJ, Hermida LF, Juffe A, CastroBeiras A "Rhabdomyolysis in heart transplant patients on HMG-CoA reductase inhibitors and cyclosporine." Transplant Proc 31 (1999): 2522-3. [PMID: 10500698]
26 Southworth MR, Mauro VF "The use of HMG-CoA reductase inhibitors to prevent accelerated graft atherosclerosis in heart transplant patients." Ann Pharmacother 31 (1997): 489-91. [PMID: 9101013]
27 Vanhaecke J, Vancleemput J, Vanlierde J, Daenen W, Degeest H "Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine." Transplantation 58 (1994): 42-5. [PMID: 8036706]
28 Arnadottir M, Eriksson LO, Germershausen JI, Thysell H "Low-dose simvastatin is a well-tolerated and efficacious cholesterol-lowering agent in ciclosporin-treated kidney transplant recipients: double-blind, randomized, placebo-controlled study in 40 patients." Nephron 68 (1994): 57-62. [PMID: 7991041]