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2D Structure
Also known as: Ciclosporin, Cyclosporine, 59865-13-3, Cyclosporine a, Sandimmune, Neoral
Molecular Formula
C62H111N11O12
Molecular Weight
1202.6  g/mol
InChI Key
PMATZTZNYRCHOR-CGLBZJNRSA-N
FDA UNII
83HN0GTJ6D

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).
Cyclosporine is a Calcineurin Inhibitor Immunosuppressant. The mechanism of action of cyclosporine is as a Calcineurin Inhibitor, and Cytochrome P450 3A4 Inhibitor, and P-Glycoprotein Inhibitor.
1 2D Structure

2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
(3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(E,1R,2R)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone
2.1.2 InChI
InChI=1S/C62H111N11O12/c1-25-27-28-40(15)52(75)51-56(79)65-43(26-2)58(81)67(18)33-48(74)68(19)44(29-34(3)4)55(78)66-49(38(11)12)61(84)69(20)45(30-35(5)6)54(77)63-41(16)53(76)64-42(17)57(80)70(21)46(31-36(7)8)59(82)71(22)47(32-37(9)10)60(83)72(23)50(39(13)14)62(85)73(51)24/h25,27,34-47,49-52,75H,26,28-33H2,1-24H3,(H,63,77)(H,64,76)(H,65,79)(H,66,78)/b27-25+/t40-,41+,42-,43+,44+,45+,46+,47+,49+,50+,51+,52-/m1/s1
2.1.3 InChI Key
PMATZTZNYRCHOR-CGLBZJNRSA-N
2.1.4 Canonical SMILES
CCC1C(=O)N(CC(=O)N(C(C(=O)NC(C(=O)N(C(C(=O)NC(C(=O)NC(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N(C(C(=O)N1)C(C(C)CC=CC)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C
2.1.5 Isomeric SMILES
CC[C@H]1C(=O)N(CC(=O)N([C@H](C(=O)N[C@H](C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N([C@H](C(=O)N1)[C@@H]([C@H](C)C/C=C/C)O)C)C(C)C)C)CC(C)C)C)CC(C)C)C)C)C)CC(C)C)C)C(C)C)CC(C)C)C)C
2.2 Other Identifiers
2.2.1 UNII
83HN0GTJ6D
2.3 Synonyms
2.3.1 MeSH Synonyms

1. Ciclosporin

2. Csa Neoral

3. Csa-neoral

4. Csaneoral

5. Cya Nof

6. Cya-nof

7. Cyclosporin

8. Cyclosporine

9. Cyclosporine A

10. Neoral

11. Ol 27 400

12. Ol 27-400

13. Ol 27400

14. Sandimmun

15. Sandimmun Neoral

16. Sandimmune

2.3.2 Depositor-Supplied Synonyms

1. Ciclosporin

2. Cyclosporine

3. 59865-13-3

4. Cyclosporine A

5. Sandimmune

6. Neoral

7. Sandimmun

8. Cyclosporin

9. Ramihyphin A

10. Ciclosporine

11. Equoral

12. Gengraf

13. Neoplanta

14. Sang-35

15. Ciclosporinum

16. Sandimmun Neoral

17. Zinograf Me

18. Ciclosporina

19. Consupren

20. Mitogard

21. Optimmune

22. Ciclosporin A

23. Neurostat

24. Atopica

25. Antibiotic S 7481f1

26. Ciclosporin [inn]

27. Sangcya

28. Cyclosporine, Modified

29. Cyclosporine Microemulsion

30. Csa

31. 83hn0gtj6d

32. Sdz-oxl-400

33. Mls001333756

34. Chebi:4031

35. Antibiotic S-7481f1

36. S-neoral

37. Cipol N

38. Sigmasporin Microoral

39. Nsc-290193

40. Cyclosporin A Solution

41. Ol-27-400

42. Dsstox_cid_365

43. Mfcd00274558

44. Ciclosporin (ciclosporin A)

45. Dsstox_rid_75541

46. Dsstox_gsid_20365

47. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

48. Sdz-oxl 400

49. Ol 27-400

50. Abrammune

51. Imusporin

52. Seciera

53. Vekacia

54. Papilock Mini

55. Arpimune Me

56. Sandimmune Neoral

57. Ciclosporina Germed

58. (r-(r*,r*-(e)))-cyclic(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-3-hydroxy-n,4-dimethyl-l-2-amino-6-octenoyl-l-alpha-aminobutyryl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl)

59. Cya

60. Cyclo(((e)-(2s,3r,4r)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl)-l-2-aminobutyryl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl-l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl)

61. Smr000058578

62. Cicloral (antibiotic)

63. Cyclosporine [usan]

64. Debio088

65. Sang 35

66. Cyclosporine [usan:usp]

67. Unii-83hn0gtj6d

68. Ciclosporine [inn-french]

69. Ciclosporinum [inn-latin]

70. Ciclosporina [inn-spanish]

71. Cyclospori

72. Sigmasporin

73. Cyclokat

74. Ikervis

75. Papilock

76. Pulminiq

77. Zyclorin

78. Ciclomulsion

79. Ciclosporin;

80. Ccris 1590

81. Ciclosporin Dt

82. Consupren S

83. Nsc290193

84. Modusik-a

85. Hsdb 6881

86. 1cyn

87. 2wfj

88. 4jjm

89. Cipol-n

90. Ncgc00016890-01

91. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r,2r,4e)-1-hydroxy-2-methylhex-4-en-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,2

92. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r,2r,4e)-1-hydroxy-2-methylhex-4-en-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

93. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methyl-hex-4-enyl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

94. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methylhex-4-enyl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19

95. (r-[r*,r*-(e)])-cyclic(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-3-hydroxy-n,4-dimethyl-l-2-amino-6-octenoyl-l-alpha-aminobutyryl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl)

96. Cyclo[[(e)-(2s,3r,4r)-3-hydroxy-4-methyl-2-(methylamino)-6-octenoyl]-l-2-aminobutyryl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl-l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl]

97. Drg-0275

98. Prestwick_731

99. Cas-59865-13-3

100. Cequa

101. Verkazia

102. Nsc 290193

103. Csa & Ifn.alpha.

104. 1c5f

105. 2z6w

106. S 7481f1

107. Cyclosporine Manufacturer

108. Prestwick2_000435

109. Prestwick3_000435

110. Ciclosporin [jan]

111. Chembl160

112. Sang-2000

113. Cyclosporine [hsdb]

114. Cyclosporine [iarc]

115. Cyclosporin A [mi]

116. Schembl3491

117. Schembl4442

118. Ciclosporin [mart.]

119. Cyclosporine [vandf]

120. Nova-22007

121. Ikervis (opthalmic Solution)

122. Bspbio_000450

123. Ciclosporin [who-dd]

124. Ciclosporin [who-ip]

125. Cyclosporin A & Ifn.alpha.

126. Mls000028376

127. Mls002153454

128. Mls002207033

129. Verkazia (opthalmic Solution)

130. Cyclosporine [usp-rs]

131. Bpbio1_000496

132. Gtpl1024

133. Dtxsid0020365

134. Chebi:92233

135. Ath-002

136. Cyclosporine [green Book]

137. Olo-400

138. Cb-01-09 Mmx

139. Ciclosporin [ep Monograph]

140. Cyclosporine [orange Book]

141. Hms1569g12

142. Hms2089a09

143. Hms2096g12

144. Hms2230m14

145. Hms3713g12

146. Cyclosporine [usp Impurity]

147. 1,11-cyclo[l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-(e)-(2s,3r,4r)-2-amino-3-hydroxy-n,4-dimethyloct-6-enoyl-l-2-aminobutanoyl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucine]

148. 30-ethyl-33-(1-hydroxy-2-methyl-hex-4-enyl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31undecaaza-cyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone

149. 30-ethyl-33-[(4e)-1-hydroxy-2-methylhex-4-en-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-bis(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

150. 30-ethyl-33-[(4e)-1-hydroxy-2-methylhex-4-en-1-yl]-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone

151. Cyclo(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-((3r,4r,6e)-6,7-didehydro-3-hydroxy-n,4-dimethyl-l-2-aminooctanoyl)-l-2-aminobutanoyl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methylleucyl)

152. Cyclosporin A, Ready Made Solution

153. Ex-a4110

154. Hy-b0579

155. Cyclosporine [usp Monograph]

156. Tox21_110667

157. Tox21_301849

158. Bdbm50022815

159. Ciclosporinum [who-ip Latin]

160. De-076

161. St-603

162. Cyclosporin A, >=98.5% (tlc)

163. Akos015969287

164. Tox21_110667_1

165. Ccg-208184

166. Db00091

167. Ks-1257

168. Sdccgsbi-0050230.p004

169. Ncgc00093704-12

170. Ncgc00164258-01

171. Ncgc00164258-02

172. Ncgc00164258-03

173. Ncgc00255232-01

174. Bc164336

175. Cyclo(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-((3r,4r,6e)-6,7-didehydro-3-hydroxy-n,4-dimethyl-l-2-aminooctanoyl-l-2-aminobutanoyl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methylleucyl)

176. Ol-27400

177. Sbi-0050230.p003

178. M01532

179. 865c133

180. A832514

181. Cyclosporin A, Vetranal(tm), Analytical Standard

182. Q367700

183. Sr-01000780563

184. Q-200913

185. Sr-01000780563-3

186. Brd-k03222093-001-01-8

187. Brd-k13533483-001-03-0

188. Ciclosporin, European Pharmacopoeia (ep) Reference Standard

189. Cyclosporin A, From Tolypocladium Inflatum, >=95% (hplc), Solid

190. Cyclosporine, United States Pharmacopeia (usp) Reference Standard

191. Ciclosporin For System Suitability, European Pharmacopoeia (ep) Reference Standard

192. Cyclosporin A, From Tolypocladium Inflatum, Bioreagent, For Molecular Biology, >=95%

193. Cyclosporine, Pharmaceutical Secondary Standard; Certified Reference Material

194. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-((1r,2r,e)-1-hydroxy-2-methylhex-4-en-1-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone

195. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(1r,2r,4e)-1-hydroxy-2-methylhex-4-en-1-yl]-1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-bis(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecaazacyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecone

196. (3s,6s,9s,12r,15s,18s,21s,24s,30s,33s)-30-ethyl-33-[(e,1r,2r)-1-hydroxy-2-methyl-pent-3-enyl]-3,6,9,18,24-pentaisobutyl-21-isopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotritriacontane-2,5,8,11,14,17,20,23,26,29,32

197. (r-(r*,r*-(e)))-cyclic(l-alanyl-d-alanyl-n-methyl-l-leucyl-n-methyl-l-leucyl-n-methyl-l-valyl-3-hydroxy-n,4-dimethyl-l-2-amino-6-octenoyl-l-.alpha.-aminobutyryl-n-methylglycyl-n-methyl-l-leucyl-l-valyl-n-methyl-l-leucyl)

198. 104250-72-8

199. 30-ethyl-33-((e)-1-hydroxy-2-methyl-hex-4-enyl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,28-octamethyl-1,4,7,10,13,16,19,22,25,28,31undecaaza-cyclotritriacontan-2,5,8,11,14,17,20,23,26,29,32-undecaone

2.4 Create Date
2005-11-20
3 Chemical and Physical Properties
Molecular Weight 1202.6 g/mol
Molecular Formula C62H111N11O12
XLogP37.5
Hydrogen Bond Donor Count5
Hydrogen Bond Acceptor Count12
Rotatable Bond Count15
Exact Mass1201.84136802 g/mol
Monoisotopic Mass1201.84136802 g/mol
Topological Polar Surface Area279 Ų
Heavy Atom Count85
Formal Charge0
Complexity2330
Isotope Atom Count0
Defined Atom Stereocenter Count12
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count1
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 8  
Drug NameCyclosporine
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormInjectable; Capsule; Solution
RouteInjection; Oral
Strength50mg/ml; 25mg; 100mg; 100mg/ml; 50mg
Market StatusPrescription
CompanyWatson Labs; Wockhardt; Ivax Sub Teva Pharms; Apotex; Luitpold; Abbvie; Eurohlth Intl; Sandoz

2 of 8  
Drug NameGengraf
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelGengraf Oral Solution (cyclosporine oral solution, USP [MODIFIED]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.Cyclosporine, the active principle in Gengraf Oral Solution, is a cyclic...
Active IngredientCyclosporine
Dosage FormCapsule
RouteOral
Strength25mg; 100mg; 50mg
Market StatusPrescription
CompanyAbbvie

3 of 8  
Drug NameNeoral
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormCapsule; Solution
RouteOral
Strength25mg; 100mg; 100mg/ml
Market StatusPrescription
CompanyNovartis

4 of 8  
Drug NameSandimmune
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormCapsule; Injectable; Solution
RouteInjection; Oral
Strength25mg; 50mg/ml; 100mg; 100mg/ml; 50mg
Market StatusPrescription
CompanyNovartis

5 of 8  
Drug NameCyclosporine
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormInjectable; Capsule; Solution
RouteInjection; Oral
Strength50mg/ml; 25mg; 100mg; 100mg/ml; 50mg
Market StatusPrescription
CompanyWatson Labs; Wockhardt; Ivax Sub Teva Pharms; Apotex; Luitpold; Abbvie; Eurohlth Intl; Sandoz

6 of 8  
Drug NameGengraf
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelGengraf Oral Solution (cyclosporine oral solution, USP [MODIFIED]) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.Cyclosporine, the active principle in Gengraf Oral Solution, is a cyclic...
Active IngredientCyclosporine
Dosage FormCapsule
RouteOral
Strength25mg; 100mg; 50mg
Market StatusPrescription
CompanyAbbvie

7 of 8  
Drug NameNeoral
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormCapsule; Solution
RouteOral
Strength25mg; 100mg; 100mg/ml
Market StatusPrescription
CompanyNovartis

8 of 8  
Drug NameSandimmune
PubMed HealthCyclosporine
Drug ClassesAnti-Inflammatory, Immune Suppressant
Drug LabelCyclosporine, the active principle in Sandimmune (cyclosporine) is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.Chemically, cyclosporine is designate...
Active IngredientCyclosporine
Dosage FormCapsule; Injectable; Solution
RouteInjection; Oral
Strength25mg; 50mg/ml; 100mg; 100mg/ml; 50mg
Market StatusPrescription
CompanyNovartis

4.2 Therapeutic Uses

Clinical indications for cyclosporine are kidney, liver, heart, & other organ transplantation; rheumatoid arthritis; & psoriasis. ... Cyclosporine usually is used in combination with other agents, especially glucocorticoids & either azathioprine or mycophenolate mofetil &, most recently, sirolimus. ... In rheumatoid arthritis, cyclosporine is used in cases of severe disease that have not responded to methotrexate. Cyclosporine can be used in combination with methotrexate, but the levels of both drugs must be monitored closely. In psoriasis, cyclosporine is indicated for treatment of adult nonimmunocompromised patients with severe & disabling disease who have failed other systemic therapies. Because of its mechanism of action, there is a theoretical bases for the use of cyclosporine in a variety of other T-cell-mediated diseases. Cyclosporine has been reported to be effective in Behcet's acute ocular syndrome, endogenous uveitis, atopic dermatitis, inflammatory bowel disease, & nephrotic syndrome when standard therapies have failed.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1468


For prevention of allograft rejection in adults and children ... .

Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 780


Cyclosporine is indicated, usually in combination with corticosteroids, for prevention of rejection of renal, hepatic, and cardiac transplants (allografts). /Included in US product labeling/

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


Cyclosporine is also indicated for prevention of rejection of heart-lung and pancreatic transplants. /NOT included in US product labeling/

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


For more Therapeutic Uses (Complete) data for CYCLOSPORIN A (13 total), please visit the HSDB record page.


4.3 Drug Warning

Non-PVC containers & administration sets should be used to administer cyclosporine solns. ... Use of glass containers & tubing that does not contain DEHP to administer cyclosporine was recommended.

Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996., p. 308


Cyclosporine is distributed into breast milk. Mothers taking cyclosporine should not breast-feed their babies, because of the potential risk of serious adverse effects (e.g., hypertension, nephrotoxicity, malignancy) in the infant.

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


Appropriate studies performed to date in pediatric patients receiving cyclosporine for organ transplantation have not demonstrated pediatrics-specific problems that would limit the usefulness of cyclosporine in children. Cyclosporine has been used in pediatric patients 1 year of age and older receiving organ transplantations. Pediatric patients have increased clearance of cyclosporine as compared with adult patients. The safety and efficacy of cyclosporine to treat psoriasis and rheumatoid arthritis in pediatric patients have not been established.

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


Geriatric patients were included in the clinical trials of cyclosporine to treat rheumatoid arthritis. Geriatric patients were more likely to experience hypertension and increases in serum creatinine concentrations than were younger adult patients.

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


For more Drug Warnings (Complete) data for CYCLOSPORIN A (30 total), please visit the HSDB record page.


4.4 Drug Indication

Cyclosporine is approved for a variety of conditions. Firstly, it is approved for the prophylaxis of organ rejection in allogeneic kidney, liver, and heart transplants. It is also used to prevent bone marrow transplant rejection. For the above indications, cyclosporine can be used in conjunction with azathioprine and corticosteroids. Finally, cyclosporine can be used in patients who have chronic transplant rejection and have received previous immunosuppressive therapy and to prevent or treat graft-versus-host disease (GVHD). Secondly, cyclosporine is used for the treatment of patients with severe active rheumatoid arthritis (RA) when they no longer respond to methotrexate alone. It can be used for the treatment of adult non-immunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated. The ophthalmic solution of cyclosporine is indicated to increase tear production in patients suffering from keratoconjunctivitis sicca. In addition, cyclosporine is approved for the treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases which may include minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis. A cyclosporine ophthalmic emulsion is indicated in the treatment of vernal keratoconjunctivitis in adults and children. Off-label, cyclosporine is commonly used for the treatment of various autoimmune and inflammatory conditions such as atopic dermatitis, blistering disorders, ulcerative colitis, juvenile rheumatoid arthritis, uveitis, connective tissue diseases, as well as idiopathic thrombocytopenic purpura.


FDA Label


Treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.


Treatment of severe vernal keratoconjunctivitis (VKC) in children from 4 years of age and adolescents.


Treatment of dry eye disease


Treatment of dry eye disease


Treatment of keratoconjunctivitis sicca


Treatment of dry eye disease


Treatment of keratoconjunctivitis sicca, Treatment of vernal keratoconjunctivitis


Treatment of atopic keratoconjunctivitis


Prevention of rejection following lung transplantation


5 Pharmacology and Biochemistry
5.1 Pharmacology

Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity.


5.2 MeSH Pharmacological Classification

Enzyme Inhibitors

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)


Antirheumatic Agents

Drugs that are used to treat RHEUMATOID ARTHRITIS. (See all compounds classified as Antirheumatic Agents.)


Calcineurin Inhibitors

Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN. (See all compounds classified as Calcineurin Inhibitors.)


Dermatologic Agents

Drugs used to treat or prevent skin disorders or for the routine care of skin. (See all compounds classified as Dermatologic Agents.)


Immunosuppressive Agents

Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging. (See all compounds classified as Immunosuppressive Agents.)


Antifungal Agents

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. (See all compounds classified as Antifungal Agents.)


5.3 FDA Pharmacological Classification
5.3.1 Active Moiety
CYCLOSPORINE
5.3.2 FDA UNII
83HN0GTJ6D
5.3.3 Pharmacological Classes
Calcineurin Inhibitors [MoA]; Cytochrome P450 3A4 Inhibitors [MoA]; P-Glycoprotein Inhibitors [MoA]; Calcineurin Inhibitor Immunosuppressant [EPC]
5.4 ATC Code

S01XA18


S01XA18


L04AD01

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355


L - Antineoplastic and immunomodulating agents

L04 - Immunosuppressants

L04A - Immunosuppressants

L04AD - Calcineurin inhibitors

L04AD01 - Ciclosporin


S - Sensory organs

S01 - Ophthalmologicals

S01X - Other ophthalmologicals

S01XA - Other ophthalmologicals

S01XA18 - Ciclosporin


5.5 Absorption, Distribution and Excretion

Absorption

The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose. The Cmax of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability.


Route of Elimination

After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine.


Volume of Distribution

The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier.


Clearance

Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h.


Following oral admin of cyclosporine, the time to peak blood concns is 1.5-2.0 hr. Admin with food both delays & decreases absorption. High & low fat meals consumed within 30 min of admin decr the AUC by approx 13% & the max concn by 33%. This makes it imperative to individualize dosage regimens for outpatients. Cyclosporine is distributed extensively outside the vascular compartment. After iv dosing, the steady-state volume of distribution has been reported to be as high as 3-5 liters/kg in solid-organ transplant recipients. Only 0.1% of cyclosporine is excreted unchanged in urine. ... Cyclosporine & its metabolites are excreted principally through the bile into the feces, with only approx 6% being excreted in the urine. Cyclosporine also is excreted in human milk.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1468


... Absorption of cyclosporine is incomplete following oral admin. The extent of absorption depends upon several variables, including the individual patient & formulation used. The elimination of cyclosporine form the blood is generally biphasic, with a terminal half-life of 5-18 hr. After iv infusion, clearance is approx 5-7 ml/min/kg in adult recipients of renal transplants, but results differ by age & patient populations. For example, clearance is slower in cardiac transplant patients & more rapid in children. The relationship between admin dose & the area under the plasma concn-vs-time curve is linear within the therapeutic range, but the intersubject variability is so large that individual monitoring is required.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1468


Clinicians can administer cyclosporine by continuous iv infusion during the first few days after transplantation, then orally by twice-daily doses, to achieve plasma cyclosporine concns (measured by HPLC) of 75-150 ng/ml (equivalent to whole blood cyclosporine concns of 300-600 ng/ml measured by radioimmunoassay). It appears safe to maintain a trough plasma cyclosporine concn of about 75-150 ng/ml; however, this does not necessarily guarantee safety from nephrotoxicity. Because of preferential distribution of cyclosporine & its metabolites into red blood cells, blood levels are generally higher than plasma levels. When blood cyclosporine levels are 300-600 ng/ml by radioimmunoassay, cerebrospinal fluid levels range from 10-50 ng/ml. The apparent volume of distribution in children under 10 yr of age is about 35 l/kg, & in adults, 4.7 l/kg.

Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 780


The elimination half-life of an oral cyclosporine dose of 350 mg is 8.9 hr; after a 1400 mg dose, the half-life is 11.9 hr. Elimination occurs predominantly by metab in the liver to form 18-25 metabolites. Metabolites of cyclosporine possess little immunosuppressive activity. Cyclosporine is extensively metabolized in the liver by cytochrome P450IIIA oxidase; however, neurotoxicity & possibly nephrotoxoicity usually correlate with raised blood levels of cyclosporine metabolites. Only 0.1% of a dose ix s excreted unchanged.

Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 780


For more Absorption, Distribution and Excretion (Complete) data for CYCLOSPORIN A (7 total), please visit the HSDB record page.


5.6 Metabolism/Metabolites

Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively.


Cyclosporine is extensively metabolized in the liver by the cytochrome-P450 3A (CYP3A) enzyme system & to a lesser degree by the GI tract & kidneys. At least 25 metabolites have been identified in human bile, feces, blood, & urine. Although the cyclic peptide structure of cyclosporine is relatively resistant to metab, the side chains are extensively metabolized. All of the metabolites have both reduced biological activity & toxicity compared to the parent drug.

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1468


5.7 Biological Half-Life

The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours.


5.8 Mechanism of Action

Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development.


Cyclosporine suppresses some humoral immunity but is more effective against T cell-dependent immune mechanisms such as those underlying transplant rejection & some forms of autoimmunity. It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines, including /(interleukin-2)/ IL-2, as well as expression of antiapoptotic proteins. Cyclosporine forms a complex with cyclophilin, a cytoplasmic receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFAT. When the cytoplasmic component of NFAT is dephosphorylated, it translocates to the nucleus, where it complexes with nuclear components required for complete T-cell activation, including transactivation of IL-2 & other lymphokine genes. Calcineurin enzymatic activity is inhibited following physical interaction with the cyclosporine/cyclophilin complex. This results in the blockade of NFAT dephosphorylation; thus, the cytoplasmic component of NFAT does not enter the nucleus, gene transcription is not activated, & the T lymphocyte fails to respond to specific antigenic stimulation Cyclosporine also increases expression of transforming growth fact /beta/ (TGF-B), a potent inhibitor of IL-2-stimulated T-cell proliferation & generation of cytotoxic T lymphocytes (CTL).

Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996., p. 1466


The exact mechanism of action is unknown but seems to be related to the inhibition of production and release of interleukin-2, which is a proliferative factor necessary for the induction of cytotoxic T lymphocytes in response to alloantigenic challenge, and which plays a major role in both cellular and humoral immune responses. Cyclosporine does not affect the nonspecific defense system of the most and does not cause significant myelosuppression.

MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1136


The major pharmacodynamic action of cyclosporin within T cells is calcineurin inhibition. The complex cyclophilin-cyclosporin competitively binds to the Ca(2+)- & calmodulin-dependent phosphatase calcineurin which then inhibits downstream dephosphorylation & activation of NFAT(transcription factor). The greatest calcineurin inhibition is seen 1-2 hr after admin of Neoral in parallel to the highest blood concn.

PMID:11530680 Nishi Y; Nippon Yakurigaku Zasshi 118 (2): 107-115 (2001)


Treatment of patients after organ transplantation with the immunosuppressive drug cyclosporin A (CsA) is often accompanied by impaired glucose tolerance, thus promoting the development of diabetes mellitus. ... /The authors/ show that 2-5 microM CsA diminishes glucose-induced insulin secretion of isolated mouse pancreatic islets in vitro by inhibiting glucose-stimulated oscillations of the cytoplasmic free-Ca(2+) concn [Ca(2+)](c). This effect is not due to an inhibition of calcineurin, which mediates the immunosuppressive effect of CsA, because other calcineurin inhibitors, deltamethrin & tacrolimus, did not affect the oscillations in [Ca(2+)](c) of the B-cells. The CsA-induced decr in [Ca(2+)](c) to basal values was not caused by a direct inhibition of L-type Ca(2+) channels. CsA is known to be a potent inhibitor of the mitochondrial permeability transition pore (PTP), which ... /the authors/ recently suggested to be involved in the regulation of oscillations. Consequently, CsA also inhibited the oscillations of the cell membrane potential, & it is shown that these effects could not be ascribed to cellular ATP depletion. However, the mitochondrial membrane potential Delta Psi was affected by CsA by inhibiting the oscillations in Delta Psi. ... The observed reduction in [Ca(2+)](c) could be counteracted by the K(+)(ATP) channel blocker tolbutamide, indicating that the stimulus-secretion coupling was interrupted before the closure of K(+)(ATP) channels. It is concluded that CsA alters B-cell function by inhibiting the mitochondrial PTP. This terminates the oscillatory activity that is indispensable for adequate insulin secretion. Thus, CsA acts on different targets to induce the immunosuppressive & the diabetogenic effect.

PMID:11562451 Dufer M et al; Mol Pharmacol 60 (4): 873-879 (2001)


CsA increases CTGF, collagen I, & collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.

PMID:11349731 Finckenberg P et al; Transplantation 71 (7): 951-958 (2001)