Pharmacology of Calcineurin Antagonists
M.H. Kapturczak, H.U. Meier-Kriesche, and B. Kaplan ABSTRACTCyclosporine and tacrolimus share the same pharmacodynamic property of activated T-cell suppression via inhibition of calcineurin. The introduction of these drugs to the immuno- suppressive repertoire of transplant management has greatly improved the outcomes in organ transplantation and constitutes arguably one of the major breakthroughs in modern medicine. To this date, calcineurin inhibitors are the mainstay of prevention of allograft rejection. The experience gained from the laboratory and clinical use of cyclosporine and tacrolimus has greatly advanced our knowledge about the nature of many aspects of immune response. However, the clinical practice still struggles with the shortcomings of these drugs: the significant inter- and intraindividual variability of their pharmacokinetics, the unpredictability of their pharmacodynamic effects, as well as complexity of interactions with other agents in transplant recipients. This article briefly reviews the pharmacological aspects of calcineurin antagonists as they relate to the mode of action and pharmacoki- netics as well as drug interactions and monitoring.
CYCLOSPORINE AND TACROLIMUS—two of the anti–T-lymphocyteactivity,weredescribedinlead- most potent immunosuppressives—are termed cal- ing the way to its use in animal models of transplanta- cineurin inhibitors due to their ability to inhibit this ubiq- The impressive results of those studies were uitous phosphatase. They both share similar physicochem- followed shortly thereafter by first studies in human kidney resulting in inhibition of synthesis of proinflammatory after its discovery, in November of 1983, the US Food and cytokines and interruption of the downstream sequence of Drug Administration (FDA) approved cyclosporine for events leading to allograft Both agents have treatment and/or prevention of transplant rejection. Cur- become the cornerstone of current immunosuppressive rently, cyclosporine is used for prevention of graft rejection in kidney, liver, heart, lung, and combined heart-lung transplantation. In addition, it found its place in bone marrow transplantation in prevention of graft-versus-host The introduction of cyclosporine 20 years ago to the disease as well as in treatment of autoimmune conditions repertoire of immunosuppressive drugs constitutes one of like psoriasis, atopic dermatitis, rheumatoid arthritis, and a the major breakthroughs of modern medicine. It led to a significant improvement in the outcomes of organ trans- Cyclosporine is a lipophilic cyclic endecapep- tide with one unique aminoacid in its structure. It was In the early 1980s scientists at Fujisawa Pharmaceuticals originally derived from a filamentous fungus Tolypocladium began testing fermented Streptomyces broths for their inflatum Gams in the laboratories of the Sandoz Company specific inhibitory properties on mixed lymphocyte cultures.
in Basel, Switzerland. In 1971, in the antibiotic screening process, which also included testing of various compounds for their immunosuppressive properties, Drs J. Borel and From the Department of Medicine, Division of Nephrology, H. Sta¨helin observed that a fungal extract containing cyclo- Hypertension and Transplantation, University of Florida Collegeof Medicine, Gainesville, Florida, USA.
sporine displayed not only a considerable immunosuppres- Address reprint requests to Bruce Kaplan, MD, University of sive activity but also absence of any significant cytotoxic Florida College of Medicine, Division of Nephrology, Box In 1976 the biological properties of cyclospor- 100224, 1600 SW Archer Road, Gainesville, FL 32610-0224.
ine, the first immunosuppressive agent with a specific 2004 by Elsevier Inc. All rights reserved.
360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36 (Suppl 2S), 25SϪ32S (2004) The screening resulted in discovery of a soil fungus named such a complex results in its binding to and inhibition of Streptomyces tsukubaensis in 1984, which produced a potent In the process of T-cell activation calcineurin, immunosuppressant given a code FK506 and later named which is a calmodulin-activated serine phosphatase, associ- tacrolimus (acronym for Tsukuba macrolide immunosup- ates with and dephosphorylates inactive nuclear factor of pressive). In 1987, the results of in vitro testing and first activated T cells (NFAT). This leads to NFAT translocation to the nucleus and, in association with other transcription tially, tacrolimus was evaluated in liver factors like AP-1, initiation of downstream events involved and the FDA approved it for the prevention of liver transplant rejection in April 1994. Subsequently its use was NFAT family, NFAT1, NFAT2, and NFAT4 participate in expanded onto transplantation of other as well transcriptional activation of interleukin-2 (IL-2), IL-4, and as treatment of atopic dermatitis as a topical formulation.
The drug-immunophilin complex forms an inhib- itory association with calcium-calmodulin–activated cal- cineurin, preventing its binding and activation of Cyclosporine and tacrolimus can also interfere with ac- is a cyclic, highly hydrophobic endecapeptide that con- tion of calcineurin on other substrates than NFAT. These tains one unique aminoacid N-methyl-(4R)-4-butenyl-4- methylthreonine in position 1 as well as two unusual These actions can explain some of the side effects aminoacids: sarcosine in position 3, and D-alanine in posi- tion 8. Furthermore, seven of its aminoacids are N-methyl- Unlike their inhibitory effects on transcription and ex- ated, which may explain its resistance to inactivation in pression of proinflammatory cytokines like IL-2, treatment gastrointestinal Purified cyclosporine appears as with cyclosporine or tacrolimus seems to be associated with white prismatic needles, and is neutral and only slightly an up-regulation of transforming growth factor beta (TGF- soluble in water and saturated hydrocarbons. It is highly ␤). This cytokine has significant immunosuppressive prop- soluble in lipids and other organic solvents.
but also promotes deposition of matrix proteins and development of tissue fibrosis. Calcineurin inhibitors have been shown to be associated with increased intragraft TGF-␤ levels and development of allograft fi Tacrolimus (C44H69NO12 ⅐ H2O, molecular weight 804, is a macrolide lactone antibiotic and appears as white crystals or crystalline powder. It is insoluble in water, slightly soluble in saturated hydrocarbons, and highly solu- ble in lipids and other organic solvents.
MECHANISMS OF ACTIONCalcineurin-Dependent Mechanisms Calcineurin inhibitors exert their cellular effects through (CP) bind cyclosporine and FK-binding proteins (FKBPs) bind tacrolimus. Cyclophilin A is the most abundant cyclo- philin in T lymphocytes, and the predominant tacrolimus- binding immunophilin is the FKBP12. The CPs and FKBPs are structurally unrelated but both families have a cis-trans prolyl-peptidyl isomerase activity. The binding of cyclospor- ine or tacrolimus to its respective immunophilin enhances the immunophilin’s affinity to calcineurin. Formation of These effects seem to be more pronounced for tacrolimus than and likely contribute to long-term com- enzyme. Interindividual differences in the total CYP3A4 plications associated with these agents.
activity and the large number of exogenous and endogenous substances capable of altering its function and expression explain, in part, the tremendous differences of clearance Both cyclosporine and tacrolimus have been noted to rates of cyclosporine. Another factor found to significantly suppress the immune response in calcineurin-independent contribute to these differences is the variable expression of Indeed, cyclosporine and tacrolimus interfere intestinal P-glycoprotein. P-glycoprotein is a product of not only in the calcineurin/NFAT pathways but have been multidrug resistance-1 gene responsible for transport of a shown to block both the Jun N terminal kinase and p38 wide range of xenobiotics, including calcineurin inhibitors, signaling These pathways are necessary for out of the intestinal epithelial cells, therefore reducing their activation of AP-1 among other transcription The interference with two distinct mechanisms of T-cell activa- than 30 metabolites created by hydroxylation, demethyl- tion contributes to the high specificity of immunosuppres- ation, sulfation, and cyclization at position 1 without ever disturbing the cyclic structure of All metab- olites display only minimal, if any, immunosuppressive The average half-life of cyclosporine is about 19 It is primarily excreted in bile (Ͼ90%) with less than 1% contribution of the parent drug. Urine excretion From the moment of its introduction into clinical practice, accounts for 6% of the oral cyclosporine dose, of which only cyclosporine use was plagued by highly variable and difficult 0.1% is Cyclosporine crosses the placenta to predict bioavailability. It has been amply demonstrated that the pharmacokinetic properties of cyclosporine can be of gastrointestinal milieu (bile flow, concomitant ingestion As with cyclosporine, the absorption of tacrolimus is highly variable. This leads to various blood concentration pro- fiIts bioavailability after oral administration ranges ability in intestinal absorption of cyclosporine was especially from 5% to 67% with a mean of 29% according to one study pronounced in its first oil-based formulation (Sandimmun) of transplant The absorption variability does with the absolute bioavailability of this form varying be- not visibly correlate with the type of transplanted organ or tween 1% and 89% with a mean value of 30% (reviewed by with age. The clearance, however, appears to be faster in the pediatric recipient population, requiring administration sion preparation of cyclosporine (Neoral) led to enhanced of higher Some ethnic differences were also noted.
bioavailability and more independence from bile secretion.
African-American patients, for example, require higher Neoral absorption is more rapid reaching 70% to 135% tacrolimus doses than Caucasians to reach equivalent ther- higher cyclosporine blood concentrations than Sandimmun apeutic levels of the Although the absorption of as measured by maximum blood concentration (Cmax) and tacrolimus does not seem to be bile-dependent, meals with area under the time/dose curve The correlation a moderate content of fat have been shown to reduce the between the drug dose and AUC was also noted to be In blood, following intestinal absorption, tacrolimus re- intrapatient variability in cyclosporine pharmacokinetics distributes primarily to erythrocytes. The whole-blood con- was lower for the microemulsion as compared to the oil centrations are therefore 10 to 30 times higher than that of Tacrolimus, unlike cyclosporine, does not seem Due to its strongly lipophilic properties, the majority of to associate with lipoproteins in plasma and binds to one of cyclosporine following its intestinal absorption leaves the the acute phase proteins—the ␣1-acid It bloodstream. The apparent volume of distribution of cyclo- readily passes into the fetal and to breast milk.
sporine varies between 4 and 8 Significantly Tacrolimus undergoes near complete metabolism prior higher blood concentrations of cyclosporine are noted in to its elimination. Similar to cyclosporine, the main metab- leukocyte-rich and fat-rich Within the blood- olism of tacrolimus occurs via the CYP3A4 system. The stream, cyclosporine is enriched primarily in erythrocytes exact number of metabolites is not known, but reported to (60% to 70%) and leukocytes (9%). The noncellular frac- be as high as 15 or The main pathways include tion of blood cyclosporine is carried mainly by lipoproteins demethylation and hydroxylation with main metabolite being 31-O-demethyl-tacrolimus, which also possesses im- Cyclosporine is primarily metabolized by the CYP3A4 munosuppressive Renal excretion accounts for slightly more than 2% of administered dose with less than ity of CYP3A4-mediated cyclosporine metabolism occurs in liver; however, other organs, kidneys and gut mucosa in In an analogous fashion to cyclosporine, the pharmaco- kinetic profile of tacrolimus is also affected by the intestinal concerned, tacrolimus and sirolimus have synergistic in vivo immunoinhibitory properties due the fact that both drugs inhibit separate steps in T-lymphocyte The combination of sirolimus with cyclosporine or tacrolimus has, therefore, a potential for lower toxicity through utili- Based on available literature, it is a common assumption that cyclosporine and tacrolimus drug interactions are Everolimus, which is the 40-O-hydroxyethyl derivative of As mentioned above, the pharmacokinetic pro- sirolimus, is also a substrate of both CYP3A4 and P- files of both drugs are significantly affected by complemen- glycoprotein and has, therefore, a potential for competitive tary influence of both CYP3A4 and P-glycoprotein. It is interactions with both calcineurin Since its interesting that drugs that competitively inhibit CYP3A4 biological activity is, as in case of sirolimus, synergistic to activity also usually act as P-glycoprotein inhibitors, there- those of cyclosporine and tacrolimus, combining it with fore increasing the bioavailability of calcineurin inhibitors calcineurin inhibitors may lead to overall decrease in tox- and their potential for toxicity. One commonly encountered icity without affecting transplantation al- though nephrotoxicity remains a significant problem even at drugs, like phenobarbital, known to induce CYP3A4 levels low doses of calcineurin inhibitors.
via activation of gene transcription also tend to up-regulate levels of decreasing the overall bioavail- ability of calcineurin inhibitors. This, in turn, can lead to occurrence of rejection. In addition, the complicity of the As discussed above, the use of calcineurin inhibitors is interactions is enhanced by the fact that significant age-, plagued by considerable intra- and interindividual differ- gender-, and ethnicity-related differences in the profile of ences in their pharmacokinetic properties. This makes the various drug interactions with calcineurin inhibitors have need of therapeutic drug monitoring a necessary standard of care to ensure appropriate immunosuppression with Interaction of Calcineurin Inhibitors With OtherImmunosuppressive Drugs Corticosteroids, still a part of most immunosuppressive To date, most transplant centers utilize whole-blood mea- regimens, have been shown to be substrates, inhibitors, and surements of cyclosporine trough levels as a means of inducers of as well as potent inducers of immunosuppressive monitoring. However, it has been dem- onstrated that the correlation of “therapeutic” trough levels and sample collection, corticosteroids have been shown to with the actual drug or with clinical out- either lower or increase cyclosporine requirements. The is relatively poor. The determination of total clinical importance of these interactions has been stressed AUC is the most accurate measure of drug exposure, and its but is not fully Similar concerns are very values possibly correlate to some degree with the rate of acute and chronic However, due to the cost In combination with mycophenolate mofetil, tacrolimus and inconvenience of multiple blood measurements re- has been found to be associated with significantly higher quired for AUC determination, this method is impractical mycophenolic acid (MPA) trough levels and the total MPA and several limited sampling strategies have been devel- exposure (AUC) than when it was coadministered with oped as surrogates for determination of full AUC utilizing two or three point measurements with various correlation cyclosporine decreasing rather than tacrolimus increasing Currently, prospective studies are underway ex- amining the utility of a single measurement of 2-hour (C strated that cyclosporine interferes with enterohepatic re- cyclosporine level, which has been shown recently to be circulation of MPA, an effect not observed for tacroli- associated with renal allograft The utilization Cyclosporine influences the pharmacokinetics of siroli- 2 levels for monitoring seems to be logical, as the blood concentrations of cyclosporine during the early postdose mus by increasing its bioavailability via competitive inter- period have been shown to correlate well with inhibition of calcineurin and but is logistically difficult and verse interaction is insignificant as the concentration of plagued by a high intraindividual variability.
cyclosporine is approximately 100-fold higher at the inter- action This interaction is also timing-dependent with sirolimus concentrations increased to a greater degree with concomitant cyclosporine administration than when Unlike the case of cyclosporine, the trough levels of tacroli- administered several hours Tacrolimus and siroli- mus correlate reasonably well with and are the mus have been shown to inhibit each other’s metabo- most common measure of tacrolimus treatment monitoring.
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CURRICULUM VITAE PERSONAL INFORMATION Lecturer, Department of Biomedical Engineering International University, Vietnam National Uni RESEARCH INTERESTS Controlled bioavailability of poorly water-soluble drugs, solubilization techniques, and development of nano-drug delivery systems. EDUCATION BACKGROUND From 2008 to 2011: Ph.D. Degree in Pharmaceutics , College of Pharmacy, Kangw

Ethan frome

CROMO ESAVALENTE: PRESENZA E RILEVABILITÀ NELLE Abstract: La presenza di cromo esavalente nelle acque destinate al consumo umano distribuite negli Stati Uniti ha recentemente risvegliato grosse preoccupazioni tra la popolazione a causa dell’accertata tossicità a vari livelli di questa specie. Il presente lavoro tratta i problemi correlati a tale tossicità e la conseguente ricerca di u

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