Immunosuppressive agents tacrolimus

Figure 23.3 Drug transporters in the intestinal epithelial cells. PEPT1 is the most characterized transporter for intestinal drug absorption. The basolateral peptide transporter, which is not identified at the molecular level, also plays important roles. OATP-B, OCTN2 and MRP3 may be responsible for the intestinal absorption of some drugs. On the contrary, ABC transporters such as P-gp located at brush-border membranes mediated the efflux of drugs from intestinal epithelial cells, contributing to the low bioavailabihty of drugs such as the immunosuppressive agent, tacrolimus.

Reductive ozonolysis of the double bond of the appropriate epimer of 36, followed by selective silylation of the diol produced, and radical deoxygenation of the secondary alcohol function, lead to 37, which is a derivative of the cyclohexyl unit of the immunosuppressive agent tacrolimus [20]. 

Amongst the —> immunosuppressive agents besides the —> glucocorticoids the modern nontoxic drugs have become drugs of choice including ciclosporin, tacrolimus or ascomycin. 

Selective immunosuppressive agents mycophenolate mofetil sirolimus tacrolimus... 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

For a number of overt, broad spectrum immunosuppressive xenobiotics (e.g., azathioprine) there is sufficient clinical experience to indicate the types of neoplasms for which there is an increased risk. These tumor types are listed in Table 27.1. Also listed are the tumors that occur in the unfortunate experiment of nature, namely patients infected with human immunodeficiency virus type 1 (HIV-1) and the tumors that may occur at higher incidence with more selective yet strong immunosuppressants (e.g., cyclosporin, sirolimus, and tacrolimus). Compared to the broad spectrum immunosuppressive agents listed above, most IMBPs express a highly selective regulatory influence on the immune system modulating the activity of host defense systems rather than mediating frank immunosuppression. 

Tacrolimus is a macrolide immunosuppressant agent that is isolated from a bacterium. It acts like ciclosporin and is used to protect and treat liver and kidney grafts when conventional immunosuppressants fail. Such rescue treatment may be graft-or life-saving. Tacrolimus may cause nephrotoxicity, neurotoxicity, disturbance of glucose metabolism, hyperkalaemia and hypertrophic cardiomyopathy. 

Although, at the time of discovery FK 506 was reported as a new immunosuppressant agent being 100-fold more potent than cyclosporin A, efforts to displace cyclosporin A by FK 506, commercialized as tacrolimus, failed until today. It is worth mentioning that FK 506 stimulated the setup of the venture capital funded US company Vertex that aims at a designed drug to treat HIV infections starting from FK 506 as a lead compound. 

Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus A new immunosuppressive agent. Am J Health Syst Pharm 1995 52 1521. 

Tacrolimus is a macrohde immunosuppressive agent indicated for the prevention of organ transplant rejection and useful as an alternative treatment in severe recalcitrant psoriasis. Tacrolimus, like cyclosporine, inhibits T-ceU activation. ... 

Manez R, Jain A, Marino IR, et al. Comparative evaluation of tacrolimus (FK506) and cyclosporin A as immunosuppressive agents. Transpl Rev 1995 9 63. 

It has been shown that subjects with renal diseases such as IgA nephropathy, membranous prohferative glomerulonephritis, focal sclerosis, and lupus nephritis have levels of endothelin that are significantly higher than those in healthy subjects [209]. Increased circulating ET-1 concentrations and urinary excretion of ET-1 have been observed in patients treated with the nephrotoxic immunosuppressive agents cyclosporine A and tacrolimus (FK-506) [210]. Other nephrotoxic agents, such as cisplatin, also increase urinary excretion of ET [211]. In patients with chronic renal disease, urinary excretion of ET-1 is significantly elevated when compared to normal values (Table 10). 

Nephrotoxicity, neurotoxicity (tremor, headache, motor disturbances, seizures), G1 complaints, hypertension, hyperkalemia, hyperglycemia, and diabetes are all associated with tacrolimus use. As with cyclosporine, nephrotoxicity is limiting. Tacrolimus has a negative effect on pancreatic islet beta cells, and glucose intolerance and diabetes melli-tus are well-recognized complications of tacrolimus-based immunosuppression. As with other immunosuppressive agents, there is an increased risk of secondary tumors and opportunistic infections. Notably, tacrolimus does not adversely affect uric acid or LDL cholesterol. 

Based on the different mechanism of action from cyclosporin and tacrolimus, rapamycin has been investigated as an adjunctive immunosuppressant agent for prevention of rejection after organ transplantation in combination with these agents. 

PRES is a syndrome that results from loss of cerebral autoregulation and capillary leakage in association with a variety of clinical entities including acute hypertension preeclampsia and eclampsia septic shock autoimmune diseases such as systemic lupus erythematosus and Wegener granulomatosis treatment with immunosuppressive agents snch as cyclosporin and tacrolimus treatment with chemotherapentic agents such as intrathecal... 

The fungal-derived cyclic peptide cyclosporine (cyclosporin A) was found some years ago to be an immunosuppressive agent in organ and tissue transplant surgery. Another compound with this same type of use and that also acts by the inhibition of T-cell activation is the macrolide tacrolimus (FK-506), from Streptomyces tsukubaensis (2). 

Tacrolimus (FK-506) is an extremely effective immunosuppressive agent, being approximately 100 times more active than cyclosporine A (Kino et al. 1987). Its mechanism of action is quite similar to that of cyclosporines. Tacrolimus binds to immunophilin FKproteinl2, and this binary complex inhibits calcineurin, which is responsible for activating the transcription of interleukin-2 (Liu et al. 1991). It was approved by FDA in 1994 for use in liver transplantation. Subsequently, its use has been extended to include bone marrow, cornea, heart, lung, and other transplants (O Fig. 9.11). 

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