Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

https://science.sciencemag.org/content/sci/226/4674/544.full.pdf

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Calcineurin Inhibitor Nephrotoxicity

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840020516

Evolution of Liver Transplantation

Cyclosporin (cyclosporin A) is a unique immunosuppressant used to prevent the rejection of transplanted organs and to treat diseases of autoimmune origin. Therapeutic drug monitoring of cyclosporin is essential for several reasons: (a) wide variability in cyclosporin pharmacokinetics has been observed after the oral or intravenous administration of the drug. The variability in the kinetics of cyclosporin is related to a patient’s disease state, the type of organ transplant, the age of the patient and therapy with other drugs that interact with cyclosporin; (b) maintaining a blood concentration of cyclosporin required to prevent rejection of the transplanted organ; (c) minimising drug toxicity by maintaining trough concentrations below that which toxicity is most likely to occur; and (d) monitoring for compliance since patient non-compliance with drug regimens is a significant reason for graft loss after 60 days. Clinical monitoring and pharmacokinetic studies of cyclosporin can be performed using different biological fluids (plasma, serum or whole blood) and different analytical techniques (radioimmunoassay or high pressure liquid chromatography). The available analytical methods provide different results when using blood, plasma, or serum. Comparison of therapeutic ranges and pharmacokinetic parameters should be made with careful attention given to the method of cyclosporin analysis.

Clinical Pharmacokinetics of Cyclosporin

Cyclosporin is a powerful immunosuppressive drug used in transplantation medicine and to treat autoimmune diseases. It is a lipophilic molecule, with its bioavailability dependent on food, bile and other interacting factors. Cyclosporin is extensively metabolised in the liver by the cytochrome P450 3A system, which is subject to considerable interindividual variation.

Cyclosporin clinical pharmacokinetics

We describe a simplified isocratic "high-performance" liquid-chromatographic method for measuring a new immunosuppressive drug, cyclosporin A, in biological fluids with use of its analogs cyclosporin C and cyclosporin D as internal standards. The method is reproducible and accurate and appears to be specific for cyclosporin A; the detection limit is 31 micrograms/L. The chromatographic measurements of the concentration of cyclosporin A in serum of patients receiving the drug were invariably lower than those by radioimmunoassay and the difference became more pronounced the greater the period of time after dosing. Because measurements of cyclosporin A in serum standards were almost identical with both techniques, the differences between the two sets of results for patients' samples suggests that the radioimmunoassay is nonspecific and measures metabolites of cyclosporin A.

Simplified liquid-chromotographic analysis for cyclosporin A, and comparison with radioimmunoassay.

The effects and side effects of cyclosporine: relationship to drug pharmacokinetics.

Ciclosporin (CyA) is a potent immunosuppressive agent which acts selectively upon the immune response by inhibition of the lymphokine cascade, thus inhibiting cell-cell communication [1]. In addition, augmentation of the inflammatory response is attenuated by blockade of macrophage migration inhibition factor (MIF) and macrophage arming factor (MAF), limiting the delayed-type hypersensitivity response and immunologically nonspecific tissue injury [2]. By virtue of its efficacy and immunologic specificity, CyA is employed extensively in organ transplantation, and also appears to be of major potential importance in the area of auto-immunity.

Pharmacokinetics and Interactions of Ciclosporin

Pretransplant immunologic reactivity to donor lymphocytes--lack of correlation with posttransplant events.

Immunological and pharmacological monitoring in the clinical use of cyclosporin A.

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