Doi:10.1016/j.transproceed.2004.01.018

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.
In addition, as far as the biological activity is Measurements at other time points, for instance C2 levels, did not show better correlation with AUC than trough 15. Calne RY, Rolles K, White DJ, et al: Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 2:1033, 1979 16. Powles RL, Barrett AJ, Clink H, et al: Cyclosporin A for the treatment of graft-versus-host disease in man. Lancet 2:1327, 1978 17. Kino T, Hatanaka H, Miyata S, et al: FK-506, a novel There is little doubt that over the last 20 years calcineurin immunosuppressant isolated from a Streptomyces. II. Immunosup- inhibitors have usurped an as yet uncontested hegemony as pressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40:1256, 1987 a part of prevention of transplant rejection. Since their 18. Kino T, Hatanaka H, Hashimoto M, et al: FK 506, a novel introduction, the field of transplantation has left the roam immunosuppressant isolated from a Streptomyces. I. Fermenta- of hawkish experimentation and become a universally ac- tion, isolation, and physico-chemical and biological characteristics.
cepted standard of care for many otherwise terminal disor- 19. Ochiai T, Nakajima K, Nagata M, et al: Effect of a new ders. Moreover, the use of calcineurin inhibitors has greatly immunosuppressive agent, FK 506, on heterotopic cardiac allo- advanced our knowledge about the nature of many pro- transplantation in the rat. Transplant Proc 19:1284, 1987 cesses involved in immune response. On the other hand, we 20. European FK506 Multicentre Liver Study Group: Random- have also learned about the dark side of these drugs: the ised trial comparing tacrolimus (FK506) and cyclosporin in preven- tion of liver allograft rejection. Lancet 344:423, 1994 significant inter- and intraindividual variability of their 21. The U.S. Multicenter FK506 Liver Study Group: A compar- pharmacokinetics, the unpredictability of their pharmaco- ison of tacrolimus (FK 506) and cyclosporine for immunosuppres- dynamic effects, as well as complexity of interactions with sion in liver transplantation. N Engl J Med 331:1110, 1994 other agents in transplant recipients. Although the collec- 22. Ellis D: Clinical use of tacrolimus (FK-506) in infants and tive two decade-long experience with calcineurin inhibitors children with renal transplants. Pediatr Nephrol J 9:487, 1995 23. Laskow DA, Neylan JF, Shapiro RS, et al: The role of curbs our appetite for a panacea, it also opens up new tacrolimus in adult kidney transplantation: a review. Clin Trans- venues for development of more tailored approaches to immunosuppression in individual transplant recipients.
24. Bram RJ, Hung DT, Martin PK, et al: Identification of the immunophilins capable of mediating inhibition of signal transduc- tion by cyclosporin A and FK506: roles of calcineurin binding and cellular location. Mol Cell Biol 13:4760, 1993 25. Cardenas ME, Hemenway C, Muir RS, et al: Immunophilins 1. Venkataramanan R, Jain A, Warty VW, et al: Pharmacoki- interact with calcineurin in the absence of exogenous immunosup- netics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc 23:931, 1991 26. Loh C, Carew JA, Kim J, et al: T-cell receptor stimulation 2. Clipstone NA, Crabtree GR: Identification of calcineurin as a elicits an early phase of activation and a later phase of deactivation key signaling enzyme in T-lymphocyte activation. Nature 357:695, of the transcription factor NFAT1. Mol Cell Biol 16:3945, 1996 3. Flanagan WM, Corthesy B, Bram RJ, et al: Nuclear associa- 27. Northrop JP, Ho SN, Chen L, et al: NF-AT components tion of a T-cell transcription factor blocked by FK-506 and define a family of transcription factors targeted in T-cell activation.
4. Fruman DA, Klee CB, Bierer BE, et al: Calcineurin phospha- 28. Shaw KT, Ho AM, Raghavan A, et al: Immunosuppressive tase activity in T lymphocytes is inhibited by FK 506 and cyclo- drugs prevent a rapid dephosphorylation of transcription factor sporin A. Proc Natl Acad Sci U S A 89:3686, 1992 NFAT1 in stimulated immune cells. Proc Natl Acad Sci U S A 5. O’Keefe SJ, Tamura J, Kincaid RL, et al: FK-506- and CsA-sensitive activation of the interleukin-2 promoter by cal- 29. Timmerman LA, Clipstone NA, Ho SN, et al: Rapid shut- tling of NF-AT in discrimination of Ca2ϩ signals and immunosup- 6. Kahan BD: Cyclosporine. N Engl J Med 321:1725, 1989 7. Starzl TE, Klintmalm GB, Weil R, et al: Cyclosporin A and 30. Rao A, Luo C, Hogan PG: Transcription factors of the steroid therapy in sixty-six cadaver kidney recipients. Surg Gynecol NFAT family: regulation and function. Annu Rev Immunol 15:707, 8. Terasaki PI, Cecka JM, Gjertson DW, et al: A ten-year 31. Henderson DJ, Naya I, Bundick RV, et al: Comparison of prediction for kidney transplant survival. Clin Transpl 501, 1992 the effects of FK-506, cyclosporin A and rapamycin on IL-2 9. Heusler K, Pletscher A: The controversial early history of cyclosporin. Swiss Med Wkly 131:299, 2001 32. Johansson A, Moller E: Evidence that the immunosuppres- 10. Borel JF, Feurer C, Gubler HU, et al: Biological effects of sive effects of FK506 and cyclosporine are identical. Transplanta- cyclosporin A: a new antilymphocytic agent. Agents Actions 6:468, 33. Frantz B, Nordby EC, Bren G, et al: Calcineurin acts in 11. Calne RY, White DJ, Rolles K, et al: Prolonged survival of synergy with PMA to inactivate I kappa B/MAD3, and inhibitor of pig orthotopic heart grafts treated with cyclosporin A. Lancet 34. Aperia A, Ibarra F, Svensson LB, et al: Calcineurin mediates 12. Green CJ, Allison AC: Extensive prolongation of rabbit alpha-adrenergic stimulation of Naϩ,K(ϩ)-ATPase activity in re- kidney allograft survival after short-term cyclosporin-A treatment.
nal tubule cells. Proc Natl Acad Sci U S A 89:7394, 1992 35. Tumlin JA, Sands JM: Nephron segment-specific inhibition 13. Kostakis AJ, White DJ, Calne RY: Prolongation of the rat of Naϩ/K(ϩ)-ATPase activity by cyclosporin A. Kidney Int 43:246, heart allograft survival by Cyclosporin A. ICRS Med Sci 5:280, 36. Dawson TM, Steiner JP, Dawson VL, et al: Immunosuppres- 14. Calne RY, White DJ, Thiru S, et al: Cyclosporin A in sant FK506 enhances phosphorylation of nitric oxide synthase and patients receiving renal allografts from cadaver donors. Lancet protects against glutamate neurotoxicity. Proc Natl Acad Sci U S A 37. Khanna AK, Hosenpud JD: Cyclosporine induces the ex- 59. Tan KK, Hue KL, Strickland SE, et al: Altered pharmaco- pression of the cyclin inhibitor p21. Transplantation 67:1262, 1999 kinetics of cyclosporin in heart-lung transplant recipients with 38. Cuhaci B, Kumar MS, Bloom RD, et al: Transforming cystic fibrosis. Ther Drug Monit 12:520, 1990 growth factor-beta levels in human allograft chronic fibrosis corre- 60. Noble S, Markham A: Cyclosporin. A review of the pharma- late with rate of decline in renal function. Transplantation 68:785, cokinetic properties, clinical efficacy and tolerability of a micro- emulsion-based formulation (Neoral). Drugs 50:924, 1995 39. Khanna A, Cairns V, Hosenpud JD: Tacrolimus induces 61. Kovarik JM, Mueller EA, van Bree JB, et al: Reduced inter- increased expression of transforming growth factor-beta 1 in and intraindividual variability in cyclosporine pharmacokinetics mammalian lymphoid as well as nonlymphoid cells. Transplanta- from a microemulsion formulation. J Pharm Sci 83:444, 1994 62. Mueller EA, Kovarik JM, van Bree JB, et al: Improved dose 40. Khanna A, Plummer M, Bromberek C, et al: Expression of linearity of cyclosporine pharmacokinetics from a microemulsion TGF-beta and fibrogenic genes in transplant recipients with tacroli- mus and cyclosporine nephrotoxicity. Kidney Int 62:2257, 2002 63. Kahan BD, Dunn J, Fitts C, et al: Reduced inter- and 41. Shihab FS, Tanner AM, Shao Y, et al: Expression of intrasubject variability in cyclosporine pharmacokinetics in renal TGF-beta 1 and matrix proteins is elevated in rats with chronic transplant recipients treated with a microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Trans- 42. Shin GT, Khanna A, Ding R, et al: In vivo expression of transforming growth factor-beta I in humans: stimulation by cyclo- 64. Fahr A: Cyclosporin clinical pharmacokinetics. Clin Phar- 43. Suthanthiran M, Morris RE, Strom TB: Immunosuppres- 65. Hoyer PF, Brodehl J, Ehrich JH, et al: Practical aspects in sants: cellular and molecular mechanisms of action. Am J Kidney the use of cyclosporin in paediatric nephrology. Pediatr Nephrol 44. Metcalfe S, Alexander D, Turner J: FK 506 and cyclosporin 66. Misteli C, Rey E, Pons G, et al: Pharmacokinetics of oral each block antigen-induced T cell receptor signalling that is cyclosporin A in diabetic children and adolescents. Eur J Clin dependent on CD4 co-receptor and operates in the absence of detectable cytoplasmic calcium fluxes. Transpl Int 7(Suppl 1):S549, 67. Kahan BD, Ried M, Newburger J: Pharmacokinetics of cyclosporine in human renal transplantation. Transplant Proc 45. Metcalfe S, Alexander D, Turner J: FK506 and cyclosporin A each inhibit antigen-specific signaling in the T cell line 171 in the 68. Lensmeyer GL, Wiebe DA, Carlson IH, et al: Concentra- absence of a calcium signal. Cell Immunol 158:46, 1994 tions of cyclosporin A and its metabolites in human tissues 46. Matsuda S, Moriguchi T, Koyasu S, et al: T lymphocyte activation signals for interleukin-2 production involve activation of 69. Ried M, Gibbons S, Kwork D: Cyclosporine levels in human MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to tissue of patients treated for one week to one year. Transplant Proc cyclosporin A. J Biol Chem 273:12378, 1998 47. Matsuda S, Shibasaki F, Takehana K, et al: Two distinct 70. Gupta SK, Benet LZ: High-fat meals increase the clearance action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. EMBO Rep 1:428, 2000 71. Kolansky G: Cyclosporine formulary considerations. Phar- 48. Matsuda S, Koyasu S: [A second target of cyclosporin A and FK506]. Tanpakushitsu Kakusan Koso 45:1823, 2000 72. Lemaire M, Tillement JP: Role of lipoproteins and erythro- 49. Matsuda S, Koyasu S: Mechanisms of action of cyclosporine.
cytes in the in vitro binding and distribution of cyclosporin A in the 50. Karin M: The regulation of AP-1 activity by mitogen- 73. Urien S, Zini R, Lemaire M, et al: Assessment of cyclospor- activated protein kinases. J Biol Chem 270:16483, 1995 ine A interactions with human plasma lipoproteins in vitro and in 51. Cooney GF, Habucky K, Hoppu K: Cyclosporin pharmaco- vivo in the rat. J Pharmacol Exp Ther 253:305, 1990 kinetics in paediatric transplant recipients. Clin Pharmacokinet 74. Shimada T, Yamazaki H, Mimura M, et al: Interindividual variations in human liver cytochrome P-450 enzymes involved in 52. Dunn S, Cooney G, Sommerauer J, et al: Pharmacokinetics the oxidation of drugs, carcinogens and toxic chemicals: studies of an oral solution of the microemulsion formulation of cyclospor- with liver microsomes of 30 Japanese and 30 Caucasians. J Phar- ine in maintenance pediatric liver transplant recipients. Transplan- 75. Haehner BD, Gorski JC, Vandenbranden M, et al: Bimodal 53. Lindholm A, Welsh M, Rutzky L, et al: The adverse impact distribution of renal cytochrome P450 3A activity in humans. Mol of high cyclosporine. Clearance rates on the incidences of acute rejection and graft loss. Transplantation 55:985, 1993 76. Webber IR, Peters WH, Back DJ: Cyclosporin metabolism 54. Schroeder TJ, Hariharan S, First MR: Variations in bioavail- by human gastrointestinal mucosal microsomes. Br J Clin Pharma- ability of cyclosporine and relationship to clinical outcome in renal transplant subpopulations. Transplant Proc 27:837, 1995 77. Saeki T, Ueda K, Tanigawara Y, et al: Human P-glycopro- 55. Friman S, Backman L: A new microemulsion formulation of tein transports cyclosporin A and FK506. J Biol Chem 268:6077, cyclosporin: pharmacokinetic and clinical features. Clin Pharmaco- 78. Schinkel AH, Borst P: Multidrug resistance mediated by 56. Lindholm A, Sawe J: Pharmacokinetics and therapeutic drug P-glycoproteins. Semin Cancer Biol 2:213, 1991 monitoring of immunosuppressants. Ther Drug Monit 17:570, 1995 79. Christians U, Sewing KF: Cyclosporin metabolism in trans- 57. Mehta MU, Venkataramanan R, Burckart GJ, et al: Effect plant patients. Pharmacol Ther 57:291, 1993 of bile on cyclosporin absorption in liver transplant patients. Br J 80. Radeke HH, Christians U, Sewing KF, et al: The synergistic immunosuppressive potential of cyclosporin metabolite combina- 58. Cooney GF, Fiel SB, Shaw LM, et al: Cyclosporine bioavail- tions. Int J Immunopharmacol 14:595, 1992 ability in heart-lung transplant candidates with cystic fibrosis.
81. Yee GC: Recent advances in cyclosporine pharmacokinetics.
82. Maurer G, Lemaire M: Biotransformation and distribution 103. Christians U, Jacobsen W, Benet LZ, et al: Mechanisms of in blood of cyclosporine and its metabolites. Transplant Proc 18:25, clinically relevant drug interactions associated with tacrolimus. Clin 83. Venkataramanan R, Starzl TE, Yang S: Biliary excretion of 104. Mathis AS, DiRenzo T, Friedman GS, et al: Sex and cyclosporine in liver transplant patients. Transplant Proc 17:286, ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors. Transplantation 71:1069, 2001 84. Flechner SM, Katz AR, Rogers AJ, et al: The presence of 105. Tuteja S, Alloway RR, Meier-Kriesche HU, et al: The cyclosporine in body tissues and fluids during pregnancy. Am J effect of gender on ketoconazole induced changes in tacrolimus pharmacokinetics. Transplantation 69:S163, 2000 85. Nyberg G, Haljamae U, Frisenette-Fich C, et al: Breast- 106. Rendic S, Di Carlo FJ: Human cytochrome P450 enzymes: feeding during treatment with cyclosporine. Transplantation 65: a status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29:413, 1997 86. Jain AB, Venkataramanan R, Cadoff E, et al: Effect of 107. Wacher VJ, Wu CY, Benet LZ: Overlapping substrate hepatic dysfunction and T tube clamping on FK 506 pharmacoki- specificities and tissue distribution of cytochrome P450 3A and netics and trough concentrations. Transplant Proc 22:57, 1990 P-glycoprotein: implications for drug delivery and activity in cancer 87. Jain AB, Fung JJ, Tzakis AG, et al: Comparative study of cyclosporine and FK 506 dosage requirements in adult and pedi- 108. Demeule M, Jodoin J, Beaulieu E, et al: Dexamethasone atric orthotopic liver transplant patients. Transplant Proc 23:2763, modulation of multidrug transporters in normal tissues. FEBS Lett 88. Furukawa H, Imventarza O, Venkataramanan R, et al: The 109. Salphati L, Benet LZ: Modulation of P-glycoprotein ex- effect of bile duct ligation and bile diversion on FK506 pharmaco- pression by cytochrome P450 3A inducers in male and female rat kinetics in dogs. Transplantation 53:722, 1992 89. Neylan JF: Racial differences in renal transplantation after 110. Campana C, Regazzi MB, Buggia I, et al: Clinically signif- immunosuppression with tacrolimus versus cyclosporine. FK506 icant drug interactions with cyclosporin. An update. Clin Pharma- Kidney Transplant Study Group. Transplantation 65:515, 1998 90. Neylan JF: Effect of race and immunosuppression in renal 111. Hubner GI, Eismann R, Sziegoleit W: Drug interaction transplantation: three-year survival results from a US multicenter, between mycophenolate mofetil and tacrolimus detectable within randomized trial. FK506 Kidney Transplant Study Group. Trans- therapeutic mycophenolic acid monitoring in renal transplant 91. Beysens AJ, Wijnen RM, Beuman GH, et al: FK 506: 112. Zucker K, Rosen A, Tsaroucha A, et al: Unexpected monitoring in plasma or in whole blood? Transplant Proc 23:2745, augmentation of mycophenolic acid pharmacokinetics in renal transplant patients receiving tacrolimus and mycophenolate 92. Jusko WJ, D’Ambrosio R: Monitoring FK 506 concentra- mofetil in combination therapy, and analogous in vitro findings.
tions in plasma and whole blood. Transplant Proc 23:2732, 1991 93. Kay JE, Sampare-Kwateng E, Geraghty F, et al: Uptake of 113. Filler G, Zimmering M, Mai I: Pharmacokinetics of myco- FK 506 by lymphocytes and erythrocytes. Transplant Proc 23:2760, phenolate mofetil are influenced by concomitant immunosuppres- 94. Warty V, Venkataramanan R, Zendehrouh P, et al: Distri- 114. Vidal E, Cantarell C, Capdevila L, et al: Mycophenolate bution of FK 506 in plasma lipoproteins in transplant patients.
mofetil pharmacokinetics in transplant patients receiving cyclo- sporine or tacrolimus in combination therapy. Pharmacol Toxicol 95. Wijnen RM, Ericzon BG, Tiebosch AT, et al: Toxicity of FK 506 in the cynomolgus monkey: noncorrelation with FK 506 serum 115. van Gelder T, Klupp J, Barten MJ, et al: Comparison of the effects of tacrolimus and cyclosporine on the pharmacokinetics of 96. Venkataramanan R, Swaminathan A, Prasad T, et al: Clin- mycophenolic acid. Ther Drug Monit 23:119, 2001 ical pharmacokinetics of tacrolimus. Clin Pharmacokinet 29:404, 116. Kaplan B, Meier-Kriesche HU, Napoli KL, et al: The effects of relative timing of sirolimus and cyclosporine microemul- 97. Alak AM, Moy S: Biological activity of tacrolimus (FK506) sion formulation coadministration on the pharmacokinetics of each and its metabolites from whole blood of kidney transplant patients.
117. Lampen A, Christians U, Guengerich FP, et al: Metabolism 98. Moreno M, Latorre A, Manzanares C, et al: Clinical man- of the immunosuppressant tacrolimus in the small intestine: cyto- agement of tacrolimus drug interactions in renal transplant pa- chrome P450, drug interactions, and interindividual variability.
99. Labroo RB, Thummel KE, Kunze KL, et al: Catalytic role of 118. Lampen A, Zhang Y, Hackbarth I, et al: Metabolism and cytochrome P4503A4 in multiple pathways of alfentanil metabo- transport of the macrolide immunosuppressant sirolimus in the small intestine. J Pharmacol Exp Ther 285:1104, 1998 100. Siegsmund MJ, Cardarelli C, Aksentijevich I, et al: Keto- 119. Qi S, Xu D, Peng J, et al: Effect of tacrolimus (FK506) and conazole effectively reverses multidrug resistance in highly resistant sirolimus (rapamycin) mono- and combination therapy in prolon- gation of renal allograft survival in the monkey. Transplantation 101. Schuetz EG, Beck WT, Schuetz JD: Modulators and sub- strates of P-glycoprotein and cytochrome P4503A coordinately 120. Vu MD, Qi S, Xu D, et al: Tacrolimus (FK506) and up-regulate these proteins in human colon carcinoma cells. Mol sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the 102. Bleck JS, Thiesemann C, Kliem V, et al: Diltiazem in- creases blood concentrations of cyclized cyclosporine metabolites 121. Crowe A, Lemaire M: In vitro and in situ absorption of resulting in different cyclosporine metabolite patterns in stable SDZ-RAD using a human intestinal cell line (Caco-2) and a single male and female renal allograft recipients. Br J Clin Pharmacol pass perfusion model in rats: comparison with rapamycin. Pharm 122. Jacobsen W, Serkova N, Hausen B, et al: Comparison of 130. Kahan BD, Welsh M, Schoenberg L, et al: Variable oral the in vitro metabolism of the macrolide immunosuppressants absorption of cyclosporine. A biopharmaceutical risk factor for sirolimus and RAD. Transplant Proc 33:514, 2001 chronic renal allograft rejection. Transplantation 62:599, 1996 123. Nashan B: Early clinical experience with a novel rapamycin 131. Marsh CL: Abbreviated pharmacokinetic profiles in area- under-the-curve monitoring of cyclosporine therapy in de novo 124. Shaw LM, Holt DW, Keown P, et al: Current opinions on renal transplant patients treated with Sandimmune or Neoral.
therapeutic drug monitoring of immunosuppressive drugs. Clin Neoral study group. Ther Drug Monit 21:27, 1999 132. Pescovitz MD, Barbeito R: Two-hour post-dose cyclospor- 125. Barone G, Chang CT, Choc MGJ, et al: The pharmacoki- ine level is a better predictor than trough level of acute rejection of netics of a microemulsion formulation of cyclosporine in primary renal allograft recipients. The Neoral Study Group. Transplanta- renal allografts. Clin Transplant 16:378, 2002 133. Batiuk TD, Kung L, Halloran PP: Evidence that calcineurin 126. Lindholm A, Kahan BD: Influence of cyclosporine phar- is rate-limiting for primary human lymphocyte activation. J Clin macokinetics, trough concentrations, and AUC monitoring on outcome after kidney transplantation. Clin Pharmacol Ther 54:205, 134. Halloran PF, Helms LM, Kung L, et al: The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplan- 127. Bowers LD, Canafax DM, Singh J, et al: Studies of cyclo- sporine blood levels: analysis, clinical utility, pharmacokinetics, me- 135. Sindhi R, LaVia MF, Paulling E, et al: Stimulated response tabolites, and chronopharmacology. Transplant Proc 18:137, 1986 of peripheral lymphocytes may distinguish cyclosporine effect in 128. Nankivell BJ, Hibbins M, Chapman JR: Diagnostic utility renal transplant recipients receiving a cyclosporine ϩ rapamycin of whole blood cyclosporine measurements in renal transplantation using triple therapy. Transplantation 58:989, 1994 136. Jusko WJ, Piekoszewski W, Klintmalm GB, et al: Pharma- 129. Stiller C, Keown P: Failure of 125I-tracer selective mono- cokinetics of tacrolimus in liver transplant patients. Clin Pharmacol clonal antibody levels on a whole blood matrix to predict rejection or nephrotoxic episodes in renal transplant patients under anti- 137. Bottiger Y, Undre NA, Sawe J, et al: Effect of bile flow on lymphocyte globulin and prednisone therapy. Transplant Proc the absorption of tacrolimus in liver allograft transplantation.

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