15. Cyclosporine: Molecular Action to Clinical Therapeutics
- Bruce Kaplan MD, PhD3,4,
- Gilbert J. Burckart PharmD5,
- Fadi G. Lakkis MD6
Published Online: 19 APR 2012
DOI: 10.1002/9781444355628.ch15
Copyright © 2012 Blackwell Publishing Ltd.
Book Title
Immunotherapy in Transplantation: Principles and Practice
Additional Information
How to Cite
Strijack, B. and Keown, P. A. (2010) Cyclosporine: Molecular Action to Clinical Therapeutics, in Immunotherapy in Transplantation: Principles and Practice (eds B. Kaplan, G. J. Burckart and F. G. Lakkis), Wiley-Blackwell, Oxford, UK. doi: 10.1002/9781444355628.ch15
Editor Information
- 3
University of Arizona Medical Center Tucson, AZ, USA
- 4
Applied Genomics Center, University of Alberta Edmonton, AB, Canada
- 5
Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA
- 6
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
Publication History
- Published Online: 19 APR 2012
- Published Print: 16 APR 2010
ISBN Information
Print ISBN: 9781405182713
Online ISBN: 9781444355628
- Summary
- Chapter
- References
Keywords:
- cyclosporine;
- cyclophilin;
- calcineurin;
- cytochrome P450;
- P-glycoprotein;
- therapeutic monitoring;
- sparse sampling;
- concentration-controlled therapy;
- viral replication;
- transplantation;
- immunosuppression
Summary
The discovery of cyclosporine (CsA) enabled critical advances in transplantation, providing unique insight into the molecular mechanisms of cell signaling and immunological activation, introducing pharmacological monitoring and concentration-controlled therapy, and dramatically improving the safety and success of clinical transplantation. Inhibition of molecular events downstream of the trimolecular complex comprising cyclophilin, calcineurin A, and calcineurin B selectively inhibits T cell activation through dephosphorylation of the NFAT (nuclear factor of activated T cells). Related actions of CsA are now recognized in the replication of HIV and other viral diseases, providing novel insights to antiviral therapy. CsA has a narrow therapeutic index and complex metabolism, governed by genes encoding cytochrome P450 pathways and the ATP-binding cassette transporter P-glycoprotein, which determine absorption, distribution, metabolism, and excretion of CsA. Therapeutic monitoring and sparse-sample prediction are widely employed to optimize clinical utilization and mitigate its numerous drug–drug interactions. CsA has revolutionized clinical transplantation and forever changed outcomes and expectations in this field.