Cyclosporine with macrolides

In some ways CYP3A4 is the most important of the human isoforms. It is certainly responsible for the metabolism of more drugs and other xenobiotics than any other P450. The diversity of its substrates, which include large molecules such as steroids, cyclosporin, and macrolide antibiotics, and its continuing ability to exhibit complex non-Michaelis-Menten kinetics and cooperativity has led many to believe that the active site of this enzyme is very large with the ability to contain several substances at the same time. In 2004 the same two groups as before, at Scripps and Astex, almost simultaneously published... 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Drugs that may interact with rifabutin include the following Anticoagulants, azole antifungal agents, benzodiazepines, beta blockers, buspirone, corticosteroids, cyclosporine, delavirdine, doxycycline, hydantoins, indinavir, rifamycins, losartan, macrolide antibiotics, methadone, morphine, nelfinavir, quinine, quinidine, theophylline, aminophylline, tricyclic antidepressants, and zolpidem. 

Tacrolimus (previously known as FK506) is a macrolide antibiotic which is obtained from the fungus Streptomyces tsukubaensis. Tacrolimus binds in-tracellularly to the protein FKBP (FK binding protein) which is distinct from the protein that binds cyclosporine. However both drug-protein complexes associate in a similar way with calcineurin and inhibits its serine/threonine phosphatase activity, although the immunosuppressive potency of tacrolimus is approximately 100 fold higher than that of cyclosporine. 

Overall, however, the immensity of temperate land corresponds to a most various secondary metabolic production, different from that of tropical land. The most renowned alkaloids belong to the morphine class (Chart 6.2.A1), and, in combination with isoprenoids, to the ergot and triterpene classes (Chart 6.2. A2). Prominent in the peptides are the cyclosporins (the first of which was isolated from a fiingus collected in Norway), streptogramins, and P-lactams (Chart 6.2.P). The isoprenoids are represented by pyrethrin monoterpenes, cedrane sesquiterpenes, ginkgolide and taxane diterpenes, ophiobolane sesterterpenes, and arborane and amyrin-like triterpenes (Chart 6.2.1). In the polyketides, epothilones, recently discovered from Myxobacteria, and the long known rapamycin, are two prominent classes of macrolides (Chart 6.2.FA/PO/C). 

Tacrolimus (previously known as FK506) is a macrolide antibiotic with immunosuppressive properties very similar to cyclosporin. It is more potent than cyclosporin but the side effects are similar. Tacrolimus is a very active immunosuppressive drug both in the prevention and treatment of liver and renal allograft rejection. It is especially valuable for small bowel transplantation. 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, HIVprotease inhibitors, tacrolimus, nefazodone, fibrates, and others (see Chapter 4). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy. 

FK-506 (37) interferes with IL-2 synthesis and release and has a cyclosporin-like profile, but is considerably more potent in vitro. IC50 values are approximately 100-fold lower. This neutral macrolide suppresses the mixed lymphocyte reaction T-cell proliferation generation of cytotoxic T-cells production of T-cell derived soluble mediators, such as IL-2, IL-3, and y-IFN and IL-2 receptor expression (83). Structurally, FK-506 is similar to sirolimus. Mycophenolate mofetil (33), brequinar (34), and deoxyspeigualin are in various phases of clinical evaluation. Identification of therapeutic efficacy and safety are important factors in the determination of their utility as immunosuppressive agents. 

Reboxetine Reboxetine should not be given, even after termination of MAOI therapy. Care must be exercised when treating with antihypertensive drugs, antiar-rhythmics, cyclosporin, antipsychotics, tricyclics, fluvoxamine, antidepressants, azole antifungals, and macrolide antibacterials. 

Cyclosporine is a macrolide antibiotic and has been used as an immunosuppressive agent. Cyclosporine can cause both renal and nonrenal toxicity. Clinically renal toxicity consists of four discrete syndromes which include acute reversible renal functional impairment, delayed renal allograft function, acute vasculopathy, and chronic nephropathy with interstitial fibrosis. Proximal tubular epithelium is uniquely sensitive to the toxic effect. The toxic effect is characterized by isometric cytoplasmic vacuolations (several small equally sized vacuoles in cytoplasm), necrosis with or without subsequent mineralization, inclusion bodies (giant mitochondria), and giant lysosomes. Acute vasculopathy consists of vacuolization of the arteriolar smooth muscles and endothelial cells leading to necrosis. In some cases, thrombotic microangiopathy develops, characterized by thrombosis of the renal micro vasculature. Long-term treatment with cyclosporine results in chronic nephropathy with interstitial fibrosis (Chamey et al., 2004). 

Ryffel B, Weber E, Mihatsch MJ. Nephrotoxicity of immunosuppressants in rats comparison of macrolides with cyclosporin. Exp Nephrol 1994 2 324-333. 

Cyclosporine is a macrolide antibiotic cyclopeptide with 11 amino acids. It inhibits cytokines (primarily interleukin-2) produced by T-cells in response to antigen exposure. Cyclosporin A can be biosynthesized from soil fungus Tolypocladium inflatum or synthetically manufactured. Hazardous combustion and decomposition products of this process include carbon monoxide, carbon dioxide, nitrogen oxide, hydrogen chloride gas, and phosgene. 

Immunosuppressive drugs Azathioprine, steroids, methotrexate, macrolides (Cyclosporin A, Tacrolimus, i.e., FK506 or fujimycin, Rapamycin), deoxyspergualin Association with risk of clinical infections clearly established. Organ transplant patients are known to develop more malignancies... 

Jain A, Reyes J, Kashyap R, Rohal S, Abu-Elmagd K, Starzl T, Fung J. What have we learned about primary liver transplantation under tacrolimus immunosuppression Long-term follow-up of the first 1000 patients. Ann Surg 1999 230 441-448. Ryffel B, Weber E, Mihatsch MJ. Nephrotoxicity of immunosuppressants in rats comparison of macrolides with cyclosporin. Exp Nephrol 1994 2 324-333. 

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). 

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