Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDISP6UGAN)
  Drug Name Cyclosporine Drug Info Rifabutin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiviral Agents Antibiotics
  Structure

 Mechanism of Cyclosporine-Rifabutin Interaction (Severity Level: Major)
     Transporter induction Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cyclosporine Rifabutin
      Mechanism 1 P-gp substrate P-gp inducer
      Key Mechanism Factor 1
Factor Name P-glycoprotein 1
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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
  • Accelerated clearance of Cyclosporine due to the transporter induction by Rifabutin 
     CYP450 enzyme induction Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cyclosporine Rifabutin
      Mechanism 2 CYP450 3A4 substrate CYP450 3A4 inducer
      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
  • Increased metabolism of Cyclosporine caused by Rifabutin mediated induction of CYP450 enzyme

Recommended Action
      Management Given the risk of organ rejection associated with inadequate immunosuppressant levels, caution is advised if cyclosporine must be coadministered with rifamycins, particularly rifampin. Cyclosporine blood levels should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of rifamycin therapy in patients who are stabilized on their anti-rejection regimen.

References
1 Allen RD, Hunnisett AG, Morris PJ "Cyclosporin and rifampicin in renal transplantation." Lancet 1 (1985): 980. [PMID: 2859432]
2 Al-Sulaiman MH, Dhar JM, Al-Khader AA "Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine." Transplantation 50 (1990): 597-8. [PMID: 2219282]
3 Calne RY, White DJG, Thiru S, Rolles K, Drakopoulos S, Jamieson NV "Cyclosporin and antituberculous therapy." Lancet 1 (1985): 1342-3. [PMID: 2860539]
4 Cassidy MJ, Zyl-Smit RV, Pascoe MD, et al "Effect of rifampicin on cyclosporin A blood levels in a renal transplant recipient." Nephron 41 (1985): 207-8. [PMID: 3900779]
5 Daniels NJ, Dover JS, Schachter RK "Interaction between cyclosporin and rifampicin." Lancet 1 (1984): 639. [PMID: 6147671]
6 Hebert MF, Roberts JP, Prueksaritanont T, Benet LZ "Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction." Clin Pharmacol Ther 52 (1992): 453-7. [PMID: 1424418]
7 Howard P, Bixler TJ, Gill B "Cyclosporine-rifampin drug interaction." Drug Intell Clin Pharm 19 (1985): 763-4. [PMID: 4053986]
8 Koselj M, Bren A, Kandus A, Kovac D "Drug interactions between cyclosporine and rifampicin, erythromycin, and azoles in kidney recipients with opportunistic infections." Transplant Proc 26 (1994): 2823-4. [PMID: 7940889]
9 Langhoff E, Madsen S "Rapid metabolism of cyclosporin and prednisone in kidney transplant patient receiving tuberculostatic treatment." Lancet 2 (1983): 1031. [PMID: 6138578]
10 Modry DL, Stinson EB, Oyer PE, Jamieson SW, Baldwin JC, Shumway NE "Acute rejection and massive cyclosporin requirements in heart transplant recipients treated with rifampin." Transplantation 39 (1985): 313-4. [PMID: 3883596]
11 Offermann G, Keller F, Molzahn M "Low cyclosporine A blood levels and acute graft rejection in a renal transplant recipient during rifampin treatment." Am J Nephrol 5 (1985): 385-7. [PMID: 3904451]
12 Product Information. Sandimmune (cyclosporine). Sandoz Pharmaceuticals Corporation, East Hanover, NJ.
13 Strayhorn VA, Baciewicz AM, Self TH "Update on rifampin drug interactions, III." Arch Intern Med 157 (1997): 2453-8. [PMID: 9385296]
14 Van Buren D, Wideman CA, Ried M, et al. "The antagonistic effect of rifampin upon cyclosporin bioavailability." Transplant Proc 16 (1984): 1642-5. [PMID: 6390878]
15 Vandevelde C, Chang A, Andrews D, et al "Rifampin and ansamycin interaction with cyclosporine after renal transplantation." Pharmacotherapy 11 (1991): 88-9. [PMID: 2020617]
16 Watkins PB "Drug metabolism by cytochromes P450 in the liver and small bowel." Gastroenterol Clin North Am 21 (1992): 511-26. [PMID: 1516957]
17 Yee GC, McGuire TR "Pharmacokinetic drug interactions with cyclosporin (Part I)." Clin Pharmacokinet 19 (1990): 319-32. [PMID: 2208899]
18 Zylber-Katz E "Multiple drug interactions with cyclosporine in a heart transplant patient." Ann Pharmacother 29 (1995): 127-31. [PMID: 7756709]