Metabolic Pathway of Cyclosporine A and Its Correlation with Nephrotoxicity

Author(s): Qinghua Wu*, Kamil Kuca*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 2 , 2019

Graphical Abstract:


Background: Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. The metabolism of CsA has a close relationship with this disease in renal-transplant patients. However, the metabolic pathways of CsA and its metabolizing enzymes have rarely been comprehensively reviewed. In this review, we have summarized the specific metabolic profiles of CsA in humans, especially renal-transplant patients. Moreover, the specific metabolizing enzymes and the potential roles that CsA metabolism plays in CsA nephrotoxicity were summarized and discussed.

Methods: Electronic databases including PubMed, Web of Science, and Scifinder were searched with the keywords "Cyclosporine A and metabolism", and "Cyclosporine A and nephrotoxicity", "Cyclosporine A metabolism and nephrotoxicity". All these studies published until 2018 were included in this review.

Results: The major metabolic pathways of CsA in humans are hydroxylation and N-demethylation. Normally, these metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than that in the liver, which explains why CsA is so toxic to the kidneys. CYP3A families, especially CYP3A4 and CYP3A5, play an important role in the biotransformation of CsA. Moreover, increased lines of evidence show that some metabolites (including AM19) associate directly with nephrotoxicity in CsA-treated organ-transplant patients.

Conclusion: The findings of this review help to further understand the metabolic activities of CsA in renal-transplant patients and cast some light on the mechanisms of CsA nephrotoxicity.

Keywords: Cyclosporine A, nephrotoxicity, metabolism, metabolic pathways, metabolizing enzymes, renal-transplant patients.

Zimmermann, S.; Sekula, P.; Venhoff, M.; Motschall, E.; Knaus, J.; Schumacher, M.; Mockenhaupt, M. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: A systematic review and meta-analysis. JAMA Dermatol., 2017, 153(6), 514-522.
Ziaei, M.; Ziaei, F.; Manzouri, B. Systemic cyclosporine and corneal transplantation. Int. Ophthalmol., 2016, 36(1), 139-146.
Caires, A.; Fernandesm, G.S.; Leme, A.M.; Castino, B.; Pessoa, E.A.; Fernandes, S.M.; Fonseca, C.D.; Vattimo, M.F.; Schor, N.; Borges, F.T. Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats. Braz. J. Med. Biol. Res., 2018, 51(2), e6373.
Lai, Q.; Luo, Z.; Wu, C.; Lai, S.; Wei, H.; Li, T.; Wang, Q.; Yu, Y. Attenuation of cyclosporine A induced nephrotoxicity by schisandrin B through suppression of oxidative stress, apoptosis and autophagy. Int. Immunopharmacol., 2017, 52, 15-23.
Damiano, S.; Ciarcia, R.; Montagnaro, S.; Pagnini, U.; Garofano, T.; Capasso, G.; Florio, S.; Giordano, A. Prevention of nephrotoxicity induced by cyclosporine-A: role of antioxidants. J. Cell. Biochem., 2015, 116(3), 364-369.
Simeoni, C.; Dinicola, S.; Cucina, A.; Mascia, C.; Bizzarri, M. Systems biology approach and mathematical modeling for analyzing phase-space switch during epithelial-mesenchymal transition. Methods Mol. Biol., 2018, 1702, 95-123.
Pallet, N.; Rabant, M.; Xu-Dubois, Y.C.; Lecorre, D.; Mucchielli, M.H.; Imbeaud, S.; Agier, N.; Hertig, A.; Thervet, E.; Legendre, C.; Beaune, P.; Anglicheau, D. Response of human renal tubular cells to cyclosporine and sirolimus, a toxicogenomic study. Toxicol. Appl. Pharmacol., 2008, 229(2), 184-196.
Pallet, N.; Bouvier, N.; Bendjallabah, A.; Rabant, M.; Flinois, J.P.; Hertig, A.; Legendre, C.; Beaune, P.; Thervet, E.; Anglicheau, D. Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death. Am. J. Transplant., 2008, 8(11), 2283-2296.
Pallet, N.; Bouvier, N.; Legendre, C.; Gilleron, J.; Codogno, P.; Beaune, P.; Thervet, E.; Anglicheau, D. Autophagy protects renal tubular cells against cyclosporine toxicity. Autophagy, 2008, 4(6), 783-791.
Wirestam, L.; Frodlund, M.; Enocsson, H.; Skogh, T.; Wetterö, J.; Sjöwall, C. Osteopontin is associated with disease severity and antiphospholipid syndrome in well characterised Swedish cases of SLE. Lupus Sci. Med., 2017, 4(1), e000225.
Marchetti, P.; Navalesit, R. The metabolic effects of cyclosporin and tacrolimus. J. Endocrinol. Invest., 2000, 23, 482-490.
Fabre, G.; Bertault-Peres, P.; Fabre, I.; Maurel, P.; Just, S.; Cano, J.P. Metabolism of cyclosporin A. I. Study in freshly isolated rabbit hepatocytes. Drug Metab. Dispos., 1987, 15(3), 384-390.
Bertault-Peres, P.; Bonfils, C.; Fabre, G.; Just, S.; Cano, J.P.; Maurel, P. Metabolism of cyclosporin A. II. Implication of the macrolide antibiotic inducible cytochrome P-450 3c from rabbit liver microsomes. Drug Metab. Dispos., 1987, 15(3), 391-398.
Kolars, J.C.; Awni, W.M.; Merion, R.M.; Watkins, P.B. First-pass metabolism of cyclosporin by the gut. Lancet, 1991, 338(8781), 1488-1490.
Webber, I.R.; Back, D.J. Effect of etretinate on cyclosporin metabolism in vitro. Br. J. Dermatol., 1993, 128(1), 42-44.
Brunner, L.J.; Pai, K.S.; Munar, M.Y.; Lande, M.B.; Olyaei, A.J.; Mowry, J.A. Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients. Pediatr. Transplant., 2000, 4(4), 313-321.
Hollander, A.A.; van Rooij, J.; Lentjes, G.W.; Arbouw, F.; van Bree, J.B.; Schoemaker, R.C.; van Es, L.A.; van der Woude, F.J.; Cohen, A.F. The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients. Clin. Pharmacol. Ther., 1995, 57(3), 318-324.
Christians, U.; Sewing, K.F. Cyclosporin metabolism in transplant patients. Pharmacol. Ther., 1993, 57(2-3), 291-345.
Zheng, S.; Tasnif, Y.; Hebert, M.F.; Davis, C.L.; Shitara, Y.; Calamia, J.C.; Lin, Y.S.; Shen, D.D.; Thummel, K.E. CYP3A5 gene variation influences cyclosporine A metabolite formation and renal cyclosporine disposition. Transplantation, 2013, 95(6), 821-827.
Pham-Huy, C.; Sadeg, N.; Becue, T.; Martin, C.; Mahuzier, G.; Warnet, J.M.; Hamon, M.; Claude, J.R. In vitro metabolism of cyclosporin A with rabbit renal or hepatic microsomes: analysis by HPLC-FPIA and HPLC-MS. Arch. Toxicol., 1995, 69(5), 346-349.
Kelly, P.A.; Wang, H.; Napoli, K.L.; Kahan, B.D.; Strobel, H.W. Metabolism of cyclosporine by cytochromes P450 3A9 and 3A4. Eur. J. Drug Metab. Pharmacokinet., 1999, 24(4), 321-328.
Wong, S.; Wong, H.T.; Wacher, V.J. Minimal effect of ketoconazole on cyclosporine (SangCyA) oral absorption and first-pass metabolism in rats: evidence of a significant vehicle effect on SangCyA absorption. Biopharm. Drug Dispos., 2002, 23(2), 53-57.
Hoppu, K.; Koskimies, O.; Holmberg, C.; Hirvisalo, E.L. Evidence for pre-hepatic metabolism of oral cyclosporine in children. Br. J. Clin. Pharmacol., 1991, 32(4), 477-481.
Vickers, A.E.; Fisher, R.L.; Brendel, K.; Guertler, J.; Dannecker, R.; Keller, B.; Fischer, V. Sites of biotransformation for the cyclosporin derivative SDZ IMM 125 using human liver and kidney slices and intestine. Comparison with rat liver slices and cyclosporin A metabolism. Drug Metab. Dispos., 1995, 23(3), 327-333.
Hegazy, S.K.; Adam, A.G.; Hamdy, N.A.; Khalafallah, N.M. Effect of active infection on cytochrome P450-mediated metabolism of cyclosporine in renal transplant patients. Transpl. Infect. Dis., 2015, 17, 350-360.
Shedlofsky, S.I.; Israel, B.C.; McClain, C.J.; Hill, D.B.; Blouin, R.A. Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism. J. Clin. Invest., 1994, 94, 2209-2214.
Ma, N.; Guo, P.; Zhang, J.; He, T.; Kim, S.W.; Zhang, G.; Ma, X. Nutrients mediate intestinal bacteria mucosal immune crosstalk. Front. Immunol., 2018, 9, 5.
Fan, P.; Song, P.; Li, L.; Huang, C.; Chen, J.; Yang, W.; Qiao, S.; Wu, G.; Zhang, G.; Ma, X. Roles of Biogenic amines in intestinal signaling. Curr. Protein Pept. Sci., 2017, 18, 532-540.
Edwards, D.J.; Fitzsimmons, M.E.; Schuetz, E.G.; Yasuda, K.; Ducharme, M.P.; Warbasse, L.H.; Woster, P.M.; Schuetz, J.D.; Watkins, P. 6′,7′-Dihydroxybergamottin in grapefruit juice and Seville orange juice: effects on cyclosporine disposition, enterocyte CYP3A4, and P-glycoprotein. Clin. Pharmacol. Ther., 1999, 65(3), 237-244.
Lilja, J.J.; Kivisto, K.T.; Neuvonen, P.J. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin. Pharmacol. Ther., 2000, 68(4), 384-390.
Fanta, S.; Jönsson, S.; Karlsson, M.O.; Niemi, M.; Holmberg, C.; Hoppu, K.; Backman, J.T. Long-term changes in cyclosporine pharmacokinetics after renal transplantation in children: Evidence for saturable presystemic metabolism and effect of NR1I2 polymorphism. J. Clin. Pharmacol., 2010, 50(5), 581-597.
Ahmed, S.S.; Strobel, H.W.; Napoli, K.L.; Grevel, J. Adrenochrome reaction implicates oxygen radicals in metabolism of cyclosporine A and FK-506 in rat and human liver microsomes. J. Pharmacol. Exp. Ther., 1993, 265(3), 1047-1054.
Vickers, A.E.; Biggi, W.A.; Dannecker, R.; Fischer, V. Uptake and metabolism of cyclosporin A and SDZ IMM 125 in the human in vitro skin2 dermal and barrier function models. Life Sci., 1995, 57(3), 215-224.
Choi, C.W.; Kim, B.R.; Ohn, J.; Youn, S.W. The Advantage of cyclosporine A and methotrexate rotational therapy in long-term systemic treatment for chronic plaque psoriasis in a real world practice. Ann. Dermatol., 2017, 29(1), 55-60.
Wu, Q.; Dohnal, V.; Kuca, K.; Yuan, Z. Trichothecenes: Structure-toxic activity relationships. Curr. Drug Metab., 2013, 14(6), 641-660.
Ozbay, A.; Karamperis, N.; Jørgensen, K.A. A review of the immunosuppressive activity of cyclosporine metabolites: New insights into an old issue. Curr. Clin. Pharmacol., 2007, 2(3), 244-248.
Watkins, P.B. The role of cytochromes P-450 in cyclosporine metabolism. J. Am. Acad. Dermatol., 1990, 23(6 Pt 2), 1301-1309.
Combalbert, J.; Fabre, I.; Fabre, G.; Dalet, I.; Derancourt, J.; Cano, J.P.; Maurel, P. Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug Metab. Dispos., 1989, 17(2), 197-207.
Jäger, W.; Correia, M.A.; Bornheim, L.M.; Mahnke, A.; Hanstein, W.G.; Xue, L.; Benet, L.Z. Ethynylestradiol-mediated induction of hepatic CYP3A9 in female rats: implication for cyclosporine metabolism. Drug Metab. Dispos., 1999, 27(12), 1505-1511.
Prueksaritanont, T.; Correia, M.A.; Rettie, A.E.; Swinney, D.C.; Thomas, P.E.; Benet, L.Z. Cyclosporine metabolism by rat liver microsomes. Evidence for involvement of enzyme(s) other than cytochromes P-450 3A. Drug Metab. Dispos., 1993, 21(4), 730-737.
Hermann, M.; Kase, E.T.; Molden, E.; Christensen, H. Evaluation of microsomal incubation conditions on CYP3A4-mediated metabolism of cyclosporine A by a statistical experimental design. Curr. Drug Metab., 2006, 7(3), 265-271.
Dai, Y.; Iwanaga, K.; Lin, Y.S.; Hebert, M.F.; Davis, C.L.; Huang, W.; Kharasch, E.D.; Thummel, K.E. In vitro metabolism of cyclosporine A by human kidney CYP3A5. Biochem. Pharmacol., 2004, 68(9), 1889-1902.
Sun, B.; Guo, Y.; Gao, J.; Shi, W.F.; Fan, G.R.; Li, X.Y.; Qiu, J.X.; Qin, Y.; Liu, G.L. Influence of CYP3A and ABCB1 polymorphisms on cyclosporine concentrations in renal transplant recipients. Pharmacogenomics, 2017, 18(16), 1503-1513.
Kempkes-Koch, M.; Fobker, M.; Erren, M.; August, C.; Gerhardt, U.; Suwelack, B.; Hohage, H. Cyclosporine A metabolite AM19 as a potential biomarker in urine for CSA nephropathy. Transplant. Proc., 2001, 33(3), 2167-2169.
Sienkiewicz, B.; Hurkacz, M.; Kuriata-Kordek, M.; Augustyniak-Bartosik, H.; Wiela-Hojeńska, A.; Klinger, M. The impact of CYP3A5 on the metabolism of cyclosporine A and tacrolimus in the evaluation of efficiency and safety of immunosuppressive treatment in patients after kidney transplantation. Pharmazie, 2016, 71, 562-565.
Ikemura, K.; Urano, K.; Matsuda, H.; Mizutani, H.; Iwamoto, T.; Okuda, M. Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats, the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells. J. Pharmacol. Exp. Ther., 2009, 328(1), 249-255.
Mazzaferro, V.; Porter, K.A.; Scotti-Foglieni, C.L.; Venkataramanan, R.; Makowka, L.; Rossaro, L.; Francavilla, A.; Todo, S.; Van Thiel, D.H.; Starzl, T.E. The hepatotropic influence of cyclosporine. Surgery, 1990, 107(5), 533-539.
Provencher, S.J.; Demers, C.; Bastien, M.C.; Villeneuve, J.P.; Gascon-Barré, M. Effect of cyclosporine A on cytochrome P-450-mediated drug metabolism in the partially hepatectomized rat. Drug Metab. Dispos., 1999, 27(4), 449-455.
Bai, S.; Brunner, L.J.; Stepkowski, S.M.; Napoli, K.L.; Kahan, B.D. Effect of low dose cyclosporine and sirolimus on hepatic drug metabolism in the rat. Transplantation, 2001, 71(11), 1585-1592.
Kim, T.; Lu, S.K.; Brunner, L.J. The effect of lipoprotein-associated cyclosporine on drug metabolism and toxicity in rats. PDA J. Pharm. Sci. Technol., 2003, 57(6), 410-424.
Cooper, M.; Lindholm, P.; Pieper, G.; Seibel, R.; Moore, G.; Nakanishi, A.; Dembny, K.; Komorowski, R.; Johnson, C.; Adams, M.; Roza, A. Myocardial nuclear factor-kappaB activity and nitric oxide production in rejecting cardiac allografts. Transplantation, 1998, 66(7), 838-844.
Luan, F.L.; Zhang, H.; Schaubel, D.E.; Miles, C.D.; Cibrik, D.; Norman, S.; Ojo, A.O. Comparative risk of impaired glucose metabolism associated with cyclosporine versus tacrolimus in the late posttransplant period. Am. J. Transplant., 2008, 8(9), 1871-1877.
Cruz, F.; Wolf, A. Effects of the novel cyclosporine derivative PSC833 on glucose metabolism in rat primary cultures of neuronal and glial cells. Biochem. Pharmacol., 2001, 62(1), 129-139.
Qiu, J.; Tu, Z.; Shi, Y.; Zhang, L.; Li, Q.; Wang, W.; Ye, F.; Wang, J.; Bu, H. Interference of cyclosporine on glucose metabolism: Potential role in chronic transplantation kidney fibrosis. Transplant. Proc., 2006, 38(7), 2065-2068.
Delgado, T.C.; Barosa, C.; Nunes, P.M.; Scott, D.K.; O’Doherty, R.M.; Cerdán, S.; Geraldes, C.F.; Jones, J.G. Effect of cyclosporine A on hepatic carbohydrate metabolism and hepatic gene expression in rat. Expert Opin. Drug Metab. Toxicol., 2012, 8(10), 1223-1230.
Lopes, P.C.; Fuhrmann, A.; Sereno, J.; Espinoza, D.O.; Pereira, M.J.; Eriksson, J.W.; Reis, F.; Carvalho, E. Short and long term in vivo effects of Cyclosporine A and sirolimus on genes and proteins involved in lipid metabolism in Wistar rats. Metabolism, 2014, 63(5), 702-715.
Havrdova, T.; Jedinakova, T.; Lipar, K.; Skibova, J.; Saudek, F. Effect of tacrolimus versus cyclosporine on glucose metabolism of pancreas and kidney recipients in the late (> 8 years) posttransplant period. Transplant. Proc., 2011, 43(9), 3270-3272.
Serkova, N.; Klawitter, J.; Niemann, C.U. Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat. Transpl. Int., 2003, 16(10), 748-755.
Niemann, C.U.; Saeed, M.; Akbari, H.; Jacobsen, W.; Benet, L.Z.; Christians, U.; Serkova, N. Close association between the reduction in myocardial energy metabolism and infarct size: Dose-response assessment of cyclosporine. J. Pharmacol. Exp. Ther., 2002, 302(3), 1123-1128.
Lee, C.T.; Ng, H.Y.; Lien, Y.H.; Lai, L.W.; Wu, M.S.; Lin, C.R.; Chen, H.C. Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am. J. Nephrol., 2011, 34(1), 87-94.
Gottschalk, S.; Cummins, C.L.; Leibfritz, D.; Christians, U.; Benet, L.Z.; Serkova, N.J. Age and sex differences in the effects of the immunosuppressants cyclosporine, sirolimus and everolimus on rat brain metabolism. Neurotoxicology, 2011, 32(1), 50-57.
Wu, Q.; Wang, X.; Nepovimova, E.; Wang, Y.; Yang, H.; Kuca, K. Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings. Food Chem. Toxicol., 2018, 118, 889-907.
Ma, X.; Zhang, S.; He, L.; Rong, Y.; Briver, L.; Sun, Q.; Liu, R.; Fan, W.; Chen, S.; Yue, Z.; Kim, J.; Guan, K.; Li, D.; Zhong, Q. MTORC1- mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy, 2017, 13, 592-607.
He, L.; Zhang, J.; Zhao, J.; Ma, N.; Kim, S.W.; Qiao, S.; Ma, X. Autophagy: The last defense against cellular nutritional stress. Adv. Nutr., 2018, 9(4), 493-504.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [84 - 90]
Pages: 7
DOI: 10.2174/1389200219666181031113505
Price: $58

Article Metrics

PDF: 55
PRC: 1