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Identification
Name Cyclosporine
Accession Number DB00091 (BIOD00003, BTD00003)
Type biotech
Groups approved
Description

A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. (From Martindale, The Extra Pharmacopoeia, 30th ed).
Protein structure
Protein chemical formula C62H111N11O12
Protein average weight 1202.6112
Sequences
Synonyms
  • Ciclosporin
  • Cyclosporin
  • Cyclosporin A
  • cyclosporine
Brand names
  • Gengraf (Abbott labs)
  • Neoral (Novartis)
  • Restasis
  • Restasis (Allergan Inc)
  • Sandimmune (Novartis)
  • Sangcya
Brand name mixtures Not Available
Categories
  • Antirheumatic Agents
  • Immunomodulatory Agents
  • Enzyme Inhibitors
  • Dermatologic Agents
  • Immunosuppressive Agents
  • Antifungal Agents
CAS number 59865-13-3
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For treatment of transplant rejection, rheumatoid arthritis, severe psoriasis
Pharmacodynamics Used in immunosuppression for prophylactic treatment of organ transplants, cyclosporine exerts specific and reversible inhibition of immunocompetent lymphocytes in the G0-or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T1-helper cell is the main target, although the T1-suppressor cell may also be suppressed. Sandimmune (cyclosporine) also inhibits lymphokine production and release including interleukin-2.
Mechanism of action Cyclosporine binds to cyclophilin. The complex then inhibits calcineurin which is normally responsible for activating transcription of interleukin 2. Cyclosporine also inhibits lymphokine production and interleukin release. In ophthalmic applications, the precise mechanism of action is not known. Cyclosporine emulsion is thought to act as a partial immunomodulator in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.
Absorption The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients.
Volume of distribution Not Available
Protein binding Approximately 90% is bound to proteins, primarily lipoproteins.
Metabolism

Hepatic, extensively metabolized.

Enzyme Metabolite Reaction Km Vmax
Cytochrome P450 3A4 Metabolite AM1 hydroxylation 4 0
Route of elimination Elimination is primarily biliary with only 6% of the dose excreted in the urine. Only 0.1% of the dose is excreted in the urine as unchanged drug.
Half life Biphasic and variable, approximately 7 hours (range 7 to 19 hours) in children and approximately 19 hours (range 10 to 27 hours) in adults.
Clearance Not Available
Toxicity The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and > 1000 mg/kg in rabbits. The I.V. LD50 is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Apotex inc
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Pliva inc
  • Sandoz inc
  • Abbott laboratories
  • Novartis pharmaceuticals corp
  • Allergan inc
  • Bedford laboratories div ben venue laboratories inc
  • Pharmaforce inc
  • Novex pharma
  • Watson laboratories inc
  • Wockhardt eu operations (swiss) ag
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Liquid Intravenous
Solution Oral
Prices
Unit description Cost Unit
SandIMMUNE 100 mg/ml Solution 50ml Bottle 499.62 USD bottle
Neoral 100 mg/ml Solution 50ml Bottle 346.14 USD bottle
CycloSPORINE Modified 100 mg/ml Solution 50ml Bottle 311.53 USD bottle
SandIMMUNE 30 100 mg capsule Box 308.69 USD box
Restasis 30 0.05% Emulsion 1 Box = 30 Containers 205.99 USD box
Neoral 30 100 mg capsule Box 190.54 USD box
CycloSPORINE Modified 30 100 mg capsule Box 171.48 USD box
Gengraf 30 100 mg capsule Box 159.94 USD box
SandIMMUNE 30 25 mg capsule Box 77.33 USD box
Neoral 30 25 mg capsule Box 47.69 USD box
SandIMMUNE 50 mg/ml Solution 5ml Ampule 46.38 USD ampule
Gengraf 30 25 mg capsule Box 42.99 USD box
CycloSPORINE Modified 30 25 mg capsule Box 42.9 USD box
Cyclosporine a powder 25.2 USD g
Sandimmune 100 mg capsule 9.89 USD capsule
Sandimmune 50 mg/ml ampul 7.71 USD ml
Cyclosporine 100 mg capsule 6.46 USD capsule
Neoral 100 mg gelatn capsule 6.11 USD capsule
Cyclosporine 100 mg softgel 5.5 USD softgel capsule
Cyclosporine modif 100 mg softgel 5.5 USD softgel capsule
Cyclosporine modif 100 mg capsule 5.49 USD capsule
Cyclosporine 50 mg/ml amp 5.45 USD ml
Cyclosporine 50 mg/ml vial 5.28 USD ml
Gengraf 100 mg capsule 5.28 USD capsule
Restasis 0.05% eye emulsion 4.49 USD each
Cyclosporine 50 mg softgel 2.74 USD softgel capsule
Sandimmune 25 mg capsule 2.48 USD capsule
Cyclosporine 25 mg capsule 1.56 USD capsule
Neoral 25 mg gelatin capsule 1.53 USD capsule
Cyclosporine 25 mg softgel 1.38 USD softgel capsule
Gengraf 25 mg capsule 1.32 USD capsule
Patents
Country Patent Number Approved Expires
United States 5985321 1994-09-26 2014-09-26
United States 4839342 1992-08-02 2009-08-02
Canada 2108018 2003-04-15 2012-04-16
Canada 1332150 1994-09-27 2011-09-27
Properties
State liquid
Melting point 148-151 oC
Experimental Properties
Property Value Source
hydrophobicity 2.92 [HANSCH,C ET AL. (1995)] PhysProp
Caco2 permeability -6.05 [ADME Research, USCD] BiGG
References
Synthesis Reference Not Available
General Reference
  1. Lichtiger S, Present DH, Kornbluth A, Gelernt I, Bauer J, Galler G, Michelassi F, Hanauer S: Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994 Jun 30;330(26):1841-5. Pubmed
  2. Synthesis Information Link
  3. Pubmed
External Links
Resource Link
PharmGKB PA449167 Link_out
Drug Product Database 593257 Link_out
RxList http://www.rxlist.com/cgi/generic/cyclosporine.htm Link_out
Drugs.com http://www.drugs.com/cdi/cyclosporine-drops.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Cyclosporine Link_out
ATC Codes
  • L04AA01
AHFS Codes
  • 92:00.00
PDB Entries Not Available
FDA label show (176.1 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions
  • Avoid salt substitutes containing potassium.
  • Avoid taking with grapefruit or grapefruit juice as grapefruit can significantly increase serum levels of this product.
  • Red wine may reduce cyclosporine levels due to increased metabolism, therefore it appears prudent to avoid red wine (white wine does not appear to affect cyclosporine metabolism).
  • Take without regard to meals.
Targets

1. Calcium signal-modulating cyclophilin ligand

Pharmacological action: yes
Actions: binder

Likely involved in the mobilization of calcium as a result of the TCR/CD3 complex interaction. Binds to cyclophilin B

Organism class: human
UniProt ID: P49069 Link_out
Gene: CAMLG Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Bernasconi R, Solda T, Galli C, Pertel T, Luban J, Molinari M: Cyclosporine a-sensitive, cyclophilin B-dependent endoplasmic reticulum-associated degradation. PLoS One. 2010 Sep 28;5(9). pii: e13008. Pubmed
  4. Yamashita H, Ito T, Kato H, Asai S, Tanaka H, Nagai H, Inagaki N: Comparison of the efficacy of tacrolimus and cyclosporine A in a murine model of dinitrofluorobenzene-induced atopic dermatitis. Eur J Pharmacol. 2010 Oct 25;645(1-3):171-6. Epub 2010 Aug 3. Pubmed
  5. Galat A, Bua J: Molecular aspects of cyclophilins mediating therapeutic actions of their ligands. Cell Mol Life Sci. 2010 Oct;67(20):3467-88. Epub 2010 Jul 4. Pubmed
  6. Lee J, Kim SS: Current implications of cyclophilins in human cancers. J Exp Clin Cancer Res. 2010 Jul 19;29:97. Pubmed

2. Calcineurin subunit B isoform 2

Pharmacological action: yes
Actions: inhibitor

Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity

Organism class: human
UniProt ID: Q96LZ3 Link_out
Gene: PPP3R2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Yamashita H, Ito T, Kato H, Asai S, Tanaka H, Nagai H, Inagaki N: Comparison of the efficacy of tacrolimus and cyclosporine A in a murine model of dinitrofluorobenzene-induced atopic dermatitis. Eur J Pharmacol. 2010 Oct 25;645(1-3):171-6. Epub 2010 Aug 3. Pubmed

3. Peptidyl-prolyl cis-trans isomerase A

Pharmacological action: unknown

PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides

Organism class: human
UniProt ID: P62937 Link_out
Gene: PPIA Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Keckesova Z, Ylinen LM, Towers GJ: Cyclophilin A renders human immunodeficiency virus type 1 sensitive to Old World monkey but not human TRIM5 alpha antiviral activity. J Virol. 2006 May;80(10):4683-90. Pubmed
  2. Patwardhan AM, Jeske NA, Price TJ, Gamper N, Akopian AN, Hargreaves KM: The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11393-8. Epub 2006 Jul 18. Pubmed
  3. Redell JB, Zhao J, Dash PK: Acutely increased cyclophilin a expression after brain injury: a role in blood-brain barrier function and tissue preservation. J Neurosci Res. 2007 Jul;85(9):1980-8. Pubmed
  4. Schaller T, Ylinen LM, Webb BL, Singh S, Towers GJ: Fusion of cyclophilin A to Fv1 enables cyclosporine-sensitive restriction of human and feline immunodeficiency viruses. J Virol. 2007 Sep;81(18):10055-63. Epub 2007 Jul 3. Pubmed
  5. Lee J, Kim SS: Current implications of cyclophilins in human cancers. J Exp Clin Cancer Res. 2010 Jul 19;29:97. Pubmed
  6. Stegmann CM, Luhrmann R, Wahl MC: The crystal structure of PPIL1 bound to cyclosporine A suggests a binding mode for a linear epitope of the SKIP protein. PLoS One. 2010 Apr 2;5(4):e10013. Pubmed
Enzymes

1. Cytochrome P450 3A7

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 3A5

Actions: substrate, inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. Pubmed

4. Cytochrome P450 2C19

Actions: inhibitor

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

5. Cytochrome P450 2C8

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme responsible for the metabolism the anti- cancer drug paclitaxel (taxol)

UniProt ID: P10632 Link_out
Gene: CYP2C8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

6. Cytochrome P450 2C9

Actions: inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

7. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: substrate, inhibitor, inducer

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Romiti N, Tramonti G, Chieli E: Influence of different chemicals on MDR-1 P-glycoprotein expression and activity in the HK-2 proximal tubular cell line. Toxicol Appl Pharmacol. 2002 Sep 1;183(2):83-91. Pubmed
  2. Choo EF, Leake B, Wandel C, Imamura H, Wood AJ, Wilkinson GR, Kim RB: Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab Dispos. 2000 Jun;28(6):655-60. Pubmed
  3. Tiberghien F, Kurome T, Takesako K, Didier A, Wenandy T, Loor F: Aureobasidins: structure-activity relationships for the inhibition of the human MDR1 P-glycoprotein ABC-transporter. J Med Chem. 2000 Jun 29;43(13):2547-56. Pubmed
  4. Gao J, Murase O, Schowen RL, Aube J, Borchardt RT: A functional assay for quantitation of the apparent affinities of ligands of P-glycoprotein in Caco-2 cells. Pharm Res. 2001 Feb;18(2):171-6. Pubmed
  5. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. Pubmed
  6. Leonessa F, Kim JH, Ghiorghis A, Kulawiec RJ, Hammer C, Talebian A, Clarke R: C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump. J Med Chem. 2002 Jan 17;45(2):390-8. Pubmed
  7. Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH, Wrighton SA: Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol. 2002 May;61(5):964-73. Pubmed
  8. Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MDR1 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):765-72. Pubmed
  9. Kumar S, Kwei GY, Poon GK, Iliff SA, Wang Y, Chen Q, Franklin RB, Didolkar V, Wang RW, Yamazaki M, Chiu SH, Lin JH, Pearson PG, Baillie TA: Pharmacokinetics and interactions of a novel antagonist of chemokine receptor 5 (CCR5) with ritonavir in rats and monkeys: role of CYP3A and P-glycoprotein. J Pharmacol Exp Ther. 2003 Mar;304(3):1161-71. Pubmed
  10. Horie K, Tang F, Borchardt RT: Isolation and characterization of Caco-2 subclones expressing high levels of multidrug resistance protein efflux transporter. Pharm Res. 2003 Feb;20(2):161-8. Pubmed
  11. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. Pubmed
  12. Atkinson DE, Greenwood SL, Sibley CP, Glazier JD, Fairbairn LJ: Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer. Am J Physiol Cell Physiol. 2003 Sep;285(3):C584-91. Epub 2003 Apr 30. Pubmed
  13. Hamada A, Miyano H, Watanabe H, Saito H: Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther. 2003 Nov;307(2):824-8. Epub 2003 Sep 15. Pubmed
  14. Corea G, Fattorusso E, Lanzotti V, Taglialatela-Scafati O, Appendino G, Ballero M, Simon PN, Dumontet C, Di Pietro A: Modified jatrophane diterpenes as modulators of multidrug resistance from Euphorbia dendroides L. Bioorg Med Chem. 2003 Nov 17;11(23):5221-7. Pubmed
  15. Rao US, Scarborough GA: Direct demonstration of high affinity interactions of immunosuppressant drugs with the drug binding site of the human P-glycoprotein. Mol Pharmacol. 1994 Apr;45(4):773-6. Pubmed
  16. Pouliot JF, L’Heureux F, Liu Z, Prichard RK, Georges E: Reversal of P-glycoprotein-associated multidrug resistance by ivermectin. Biochem Pharmacol. 1997 Jan 10;53(1):17-25. Pubmed
  17. Kuhnel JM, Perrot JY, Faussat AM, Marie JP, Schwaller MA: Functional assay of multidrug resistant cells using JC-1, a carbocyanine fluorescent probe. Leukemia. 1997 Jul;11(7):1147-55. Pubmed
  18. Ito T, Yano I, Tanaka K, Inui KI: Transport of quinolone antibacterial drugs by human P-glycoprotein expressed in a kidney epithelial cell line, LLC-PK1. J Pharmacol Exp Ther. 1997 Aug;282(2):955-60. Pubmed
  19. Kim AE, Dintaman JM, Waddell DS, Silverman JA: Saquinavir, an HIV protease inhibitor, is transported by P-glycoprotein. J Pharmacol Exp Ther. 1998 Sep;286(3):1439-45. Pubmed
  20. Kusunoki N, Takara K, Tanigawara Y, Yamauchi A, Ueda K, Komada F, Ku Y, Kuroda Y, Saitoh Y, Okumura K: Inhibitory effects of a cyclosporin derivative, SDZ PSC 833, on transport of doxorubicin and vinblastine via human P-glycoprotein. Jpn J Cancer Res. 1998 Nov;89(11):1220-8. Pubmed
  21. Golstein PE, Boom A, van Geffel J, Jacobs P, Masereel B, Beauwens R: P-glycoprotein inhibition by glibenclamide and related compounds. Pflugers Arch. 1999 Apr;437(5):652-60. Pubmed
  22. Wigler PW: PSC833, cyclosporin A, and dexniguldipine effects on cellular calcein retention and inhibition of the multidrug resistance pump in human leukemic lymphoblasts. Biochem Biophys Res Commun. 1999 Apr 13;257(2):410-3. Pubmed
  23. Hochman JH, Chiba M, Nishime J, Yamazaki M, Lin JH: Influence of P-glycoprotein on the transport and metabolism of indinavir in Caco-2 cells expressing cytochrome P-450 3A4. J Pharmacol Exp Ther. 2000 Jan;292(1):310-8. Pubmed
  24. Asakura E, Nakayama H, Sugie M, Zhao YL, Nadai M, Kitaichi K, Shimizu A, Miyoshi M, Takagi K, Takagi K, Hasegawa T: Azithromycin reverses anticancer drug resistance and modifies hepatobiliary excretion of doxorubicin in rats. Eur J Pharmacol. 2004 Jan 26;484(2-3):333-9. Pubmed
  25. D’Emanuele A, Jevprasesphant R, Penny J, Attwood D: The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability. J Control Release. 2004 Mar 24;95(3):447-53. Pubmed
  26. Honda Y, Ushigome F, Koyabu N, Morimoto S, Shoyama Y, Uchiumi T, Kuwano M, Ohtani H, Sawada Y: Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux. Br J Pharmacol. 2004 Dec;143(7):856-64. Epub 2004 Oct 25. Pubmed
  27. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. Pubmed
  28. Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG: Interaction of cytochrome P450 3A inhibitors with P-glycoprotein. J Pharmacol Exp Ther. 2002 Oct;303(1):323-32. Pubmed
  29. Kugawa F, Suzuki T, Miyata M, Tomono K, Tamanoi F: Construction of a model cell line for the assay of MDR1 (multi drug resistance gene-1) substrates/inhibitors using HeLa cells. Pharmazie. 2009 May;64(5):296-300. Pubmed
  30. Dahan A, Sabit H, Amidon GL: The H2 receptor antagonist nizatidine is a P-glycoprotein substrate: characterization of its intestinal epithelial cell efflux transport. AAPS J. 2009 Jun;11(2):205-13. Epub 2009 Mar 25. Pubmed
  31. Polli JW, Wring SA, Humphreys JE, Huang L, Morgan JB, Webster LO, Serabjit-Singh CS: Rational use of in vitro P-glycoprotein assays in drug discovery. J Pharmacol Exp Ther. 2001 Nov;299(2):620-8. Pubmed
  32. Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. Pubmed
  33. Seeballuck F, Ashford MB, O’Driscoll CM: The effects of pluronics block copolymers and Cremophor EL on intestinal lipoprotein processing and the potential link with P-glycoprotein in Caco-2 cells. Pharm Res. 2003 Jul;20(7):1085-92. Pubmed
  34. Troutman MD, Thakker DR: Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003 Aug;20(8):1210-24. Pubmed
  35. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T: Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem. 1993 Mar 25;268(9):6077-80. Pubmed
  36. Fricker G, Drewe J, Huwyler J, Gutmann H, Beglinger C: Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation. Br J Pharmacol. 1996 Aug;118(7):1841-7. Pubmed
  37. Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, Watkins PB: Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther. 1997 Sep;62(3):248-60. Pubmed
  38. Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, Benet LZ: Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res. 1999 Apr;16(4):478-85. Pubmed
  39. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Loscher W: Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology. 2007 Feb;52(2):333-46. Epub 2006 Oct 10. Pubmed

2. Canalicular multispecific organic anion transporter 2

Actions: inhibitor

May act as an inducible transporter in the biliary and intestinal excretion of organic anions

UniProt ID: O15438 Link_out
Gene: ABCC3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD: Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 2001 Oct 1;61(19):7225-32. Pubmed

3. Bile salt export pump

Actions: inhibitor

Involved in the ATP-dependent secretion of bile salts into the canaliculus of hepatocytes

UniProt ID: O95342 Link_out
Gene: ABCB11 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ: The human bile salt export pump: characterization of substrate specificity and identification of inhibitors. Gastroenterology. 2002 Nov;123(5):1649-58. Pubmed
  2. Wang EJ, Casciano CN, Clement RP, Johnson WW: Fluorescent substrates of sister-P-glycoprotein (BSEP) evaluated as markers of active transport and inhibition: evidence for contingent unequal binding sites. Pharm Res. 2003 Apr;20(4):537-44. Pubmed
  3. Noe J, Hagenbuch B, Meier PJ, St-Pierre MV: Characterization of the mouse bile salt export pump overexpressed in the baculovirus system. Hepatology. 2001 May;33(5):1223-31. Pubmed
  4. Lecureur V, Sun D, Hargrove P, Schuetz EG, Kim RB, Lan LB, Schuetz JD: Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol Pharmacol. 2000 Jan;57(1):24-35. Pubmed
  5. Stieger B, Fattinger K, Madon J, Kullak-Ublick GA, Meier PJ: Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology. 2000 Feb;118(2):422-30. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

4. Multidrug resistance-associated protein 1

Actions: inhibitor

May participate directly in the active transport of drugs into subcellular organelles or influence drug distribution indirectly. Confers resistance to anticancer drugs. Transports LTC4. May protect milk against xenobiotics

UniProt ID: P33527 Link_out
Gene: ABCC1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Pec MK, Aguirre A, Fernandez JJ, Souto ML, Dorta JF, Villar J: Dehydrothyrsiferol does not modulate multidrug resistance-associated protein 1 resistance: a functional screening system for MRP1 substrates. Int J Mol Med. 2002 Nov;10(5):605-8. Pubmed
  2. Leier I, Jedlitschky G, Buchholz U, Cole SP, Deeley RG, Keppler D: The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem. 1994 Nov 11;269(45):27807-10. Pubmed

5. Solute carrier organic anion transporter family member 1A2

Actions: inhibitor

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. Pubmed

6. Ileal sodium/bile acid cotransporter

Actions: inhibitor

Plays a critical role in the sodium-dependent reabsorption of bile acids from the lumen of the small intestine. Plays a key role in cholesterol metabolism

UniProt ID: Q12908 Link_out
Gene: SLC10A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Craddock AL, Love MW, Daniel RW, Kirby LC, Walters HC, Wong MH, Dawson PA: Expression and transport properties of the human ileal and renal sodium-dependent bile acid transporter. Am J Physiol. 1998 Jan;274(1 Pt 1):G157-69. Pubmed

7. Sodium/bile acid cotransporter

Actions: inhibitor

The hepatic sodium/bile acid uptake system exhibits broad substrate specificity and transports various non-bile acid organic compounds as well. It is strictly dependent on the extracellular presence of sodium

UniProt ID: Q14973 Link_out
Gene: SLC10A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Schroeder A, Eckhardt U, Stieger B, Tynes R, Schteingart CD, Hofmann AF, Meier PJ, Hagenbuch B: Substrate specificity of the rat liver Na(+)-bile salt cotransporter in Xenopus laevis oocytes and in CHO cells. Am J Physiol. 1998 Feb;274(2 Pt 1):G370-5. Pubmed

8. Solute carrier family 22 member 6

Actions: inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sweet DH, Wolff NA, Pritchard JB: Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem. 1997 Nov 28;272(48):30088-95. Pubmed

9. Multidrug resistance-associated protein 7

Actions: inhibitor

ATP-dependent transporter probably involved in cellular detoxification through lipophilic anion extrusion

UniProt ID: Q5T3U5 Link_out
Gene: ABCC10 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen ZS, Hopper-Borge E, Belinsky MG, Shchaveleva I, Kotova E, Kruh GD: Characterization of the transport properties of human multidrug resistance protein 7 (MRP7, ABCC10). Mol Pharmacol. 2003 Feb;63(2):351-8. Pubmed

10. Canalicular multispecific organic anion transporter 1

Actions: inhibitor

Mediates hepatobiliary excretion of numerous organic anions. May function as a cellular cisplatin transporter

UniProt ID: Q92887 Link_out
Gene: ABCC2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Tang F, Horie K, Borchardt RT: Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm Res. 2002 Jun;19(6):773-9. Pubmed
  2. Hong J, Lambert JD, Lee SH, Sinko PJ, Yang CS: Involvement of multidrug resistance-associated proteins in regulating cellular levels of (-)-epigallocatechin-3-gallate and its methyl metabolites. Biochem Biophys Res Commun. 2003 Oct 10;310(1):222-7. Pubmed
  3. Kamisako T, Leier I, Cui Y, Konig J, Buchholz U, Hummel-Eisenbeiss J, Keppler D: Transport of monoglucuronosyl and bisglucuronosyl bilirubin by recombinant human and rat multidrug resistance protein 2. Hepatology. 1999 Aug;30(2):485-90. Pubmed
  4. Chen ZS, Kawabe T, Ono M, Aoki S, Sumizawa T, Furukawa T, Uchiumi T, Wada M, Kuwano M, Akiyama SI: Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol Pharmacol. 1999 Dec;56(6):1219-28. Pubmed
  5. Horikawa M, Kato Y, Tyson CA, Sugiyama Y: The potential for an interaction between MRP2 (ABCC2) and various therapeutic agents: probenecid as a candidate inhibitor of the biliary excretion of irinotecan metabolites. Drug Metab Pharmacokinet. 2002;17(1):23-33. Pubmed

11. ATP-binding cassette sub-family G member 2

Actions: inhibitor

Xenobiotic transporter that may play an important role in the exclusion of xenobiotics from the brain. May be involved in brain-to-blood efflux. Appears to play a major role in the multidrug resistance phenotype of several cancer cell lines. When overexpressed, the transfected cells become resistant to mitoxantrone, daunorubicin and doxorubicin, display diminished intracellular accumulation of daunorubicin, and manifest an ATP- dependent increase in the efflux of rhodamine 123

UniProt ID: Q9UNQ0 Link_out
Gene: ABCG2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ozvegy C, Litman T, Szakacs G, Nagy Z, Bates S, Varadi A, Sarkadi B: Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001 Jul 6;285(1):111-7. Pubmed

12. Solute carrier organic anion transporter family member 1B1

Actions: inhibitor

Mediates the Na(+)-independent transport 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. May play an important role in the clearance of bile acids and organic anions from the liver

UniProt ID: Q9Y6L6 Link_out
Gene: SLCO1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Tirona RG, Leake BF, Wolkoff AW, Kim RB: Human organic anion transporting polypeptide-C (SLC21A6) is a major determinant of rifampin-mediated pregnane X receptor activation. J Pharmacol Exp Ther. 2003 Jan;304(1):223-8. Pubmed
  2. Shitara Y, Itoh T, Sato H, Li AP, Sugiyama Y: Inhibition of transporter-mediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A. J Pharmacol Exp Ther. 2003 Feb;304(2):610-6. Pubmed
  3. Nozawa T, Tamai I, Sai Y, Nezu J, Tsuji A: Contribution of organic anion transporting polypeptide OATP-C to hepatic elimination of the opioid pentapeptide analogue [D-Ala2, D-Leu5]-enkephalin. J Pharm Pharmacol. 2003 Jul;55(7):1013-20. Pubmed
  4. Fehrenbach T, Cui Y, Faulstich H, Keppler D: Characterization of the transport of the bicyclic peptide phalloidin by human hepatic transport proteins. Naunyn Schmiedebergs Arch Pharmacol. 2003 Nov;368(5):415-20. Epub 2003 Oct 3. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 27, 2010 18:44

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.