Calcineurin inhibitor interactions

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... 

TABLE 52-6. Potential Drug-Drug Interactions with the Calcineurin Inhibitors and Sirolimus Mediated Through the CYP3A4 Isozyme11... 

Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid. Although the cytochrome P450 system is not involved, some drug interactions still occur. Plasma drug levels are frequently monitored, similar to the calcineurin inhibitors and PSIs. 

Figure 16 (a) The structure of calcmeurin with suhunit A in cyan. The catalytic site containing a Zn-Fe hinding site is in dark red. Subunit B in orange contains four calciimi (green) ions hound to the EF-hand motifs. Both N- and C-terminal domains of calcineurin B interact to the same extended a-helix of calcineurin A. (h) The inhibitor complex cyclosporin A (red) and cyclophilin (violet) interacts with both calcineurin subunits and blocks the catal)dic site of calcineurin ... 

Mathis AS, DiRenzo T, Friedman GS, Kaplan B, Adamson R. Sex and ethnicity may chiefly influence the interaction of fluconazole with calcineurin inhibitors. Transplant ation2001 71(8) 1069-75. 

Figure 2. Relative potency of the various cytochrome P450 enzymes in the metabolism of commonly prescribed proton pump inhibitors (PPi) is noted. Patients with genetic polymorphisms of the CYP2C19 pathway (poor metaboUzers) utilize the CYP3A4 pathway (dotted line) for PPi metabolism. Calcineurin inhibitors (CNI) also use the CYP3A4 pathway for their metabolism. As a result, the "poor metaboUzers" are at risk to develop elevated CNI levels when concurrently receiving a PPI. In contrast, rabeprazole is safe as it has a "non-enzymatic"pathway for its metabolism, avoiding an interaction with the CNI.

As most PPIs rely predominantly on fhe CYP2C19 pathway of metabohsm, it is understandable why these drugs are safe in studies examining normal subjects. However, since mutations in the CYP2C19 pathway exist that render the patients "poor metabolizers", a potential interaction between PPIs and calcineurin inhibitors may occur as more PPI metabohsm is shifted to the CYP3A4 enzyme. 

Renal tubular dysfunction is described in animals but human expression in unclear [12]. Most use of mTOR inhibitors is in conjunction with lowered doses of calcineurin inhibitors since it is known that these two drug classes have a potent drug-drug interaction leading to enhanced renal dysfunction compared to the calcineurin inhibitor alone [782]. This may be explained by inhibition of drug efflux pump P-glycoprotein since both siroiimus and the calcineurin inhibitors are competitive substrates [783, 784]. 

Table 3 Drugs that interact with calcineurin inhibitors Decrease concentrations of CNIs...

Sirolimus has been used to spare cyclosporine in the setting of cadaveric renal transplant since unlike the calcineurin inhibitors it is not vasoconstrictive and thus theoretically at least should be of benefit in ischemic reperfusion injury. The studies of Lieberthal mentioned above would lead one to a different strategy. Indeed there are now anecdotes appearing in the literature that similar to experimental animals, sirolimus potentiates ischemic injury following transplantation. There are few data with the combination of sirolimus and tacrolimus. However, limited information suggests that the pattern may be the same. Thus, it is clear that sirolimus used without a calcineurin inhibitor is safe from a nephrotoxic point of view but in combination with a calcineurin inhibitor there are either drug interactions or more fundamental cellular actions of sirolimus that may be adverse to renal tubular cells to impair recovery from ischemic insults such as hypotension and/or acute rejection episodes. 

Therapeutic Uses Mycophenolate mofetil is indicated for prophylaxis of transplant rejection, and it typically is used in combination with glucocorticoids and a calcineurin inhibitor, but not with azathioprine. Combined treatment with siroUmus is possible, although potential drug interactions necessitate careful monitoring of drug levels. For renal transplants, 1 g is administered orally or intravenously (over 2 hours) twice daily (2 g/day). A higher dose, 1.5 g twice daily (3 g/day), is recommended for African American renal transplant patients and all cardiac transplant patients. 

LemahieuWPD, Hermann M, Asberg A, Verbeke K, Holdaas H, Vanrenterghem Y, MaesBD. Combined therapy with atorvastatin and calcineurin inhibitors no interactions with tacrolimus. AmJ Transplant (2005) 5, 2236-43. 

High-throughput screening of one-bead-one-compound libraries identification of cyclic peptidyl inhibitors against calcineurin/NFAT interaction. 

Calcineurin inhibitors See also individual names. The interaction of oral itraconazole in solution and calcineurin inhibitors (ciclo-sporin or tacrolimus) has been retrospectively studied in 10 recipients of allogeneic hemopoietic stem cell transplants [28/]. Itraconazole significantly increased the dose-corrected blood concentrations of the... 

Mori T, Aisa Y, Kato J, Nakamura Y, Ikeda Y, Okamoto S. Drug interaction between oral solution itraconazole and calcineurin inhibitors in allogeneic hematopoietic stem cell transplantation recipients an association with bioavailability of oral solution itraconazole. Int J Hematol 2009 90 103-7. 

The possibility of drug nephrotoxicity has to be excluded, either directly caused by calcineurin inhibitors (ciclosporin, tacrolimus) or more indirectly amplified by drug interactions. Again, the definitive diagnosis is provided by the biopsy, showing acute or chronic lesions associated with calcineurin-in-hibitor-induced nephrotoxicity. 

Figure 6.17 Cartoon depicting the interactions of FKBP with inhibitor and the subsequent binding of the FKBP Inhibitor binary complex to the enzyme calcineurin (E).

Very recendy a new, physiologic inhibitor of calcineurin has been described by Liu and colleagues at MIT and OriGene (Sun et al., 1998). This protein, called cabin-1 (calcineurin binding protein) is a 2220-residue nuclear protein, which was isolated from a murine T-cell cDNA library in a yeast two-hybrid system with a truncated, catalydcally inac-dve calcineurin used as the bait. Cabin-1 was shown to be a phospho-protein capable of binding to and inhibiting the phosphatase activity of calcineurin, and the interaction between cabin-1 and calcineurin was shown to be sensitive to disruption by FK506 or CsA. In a mammalian... 

Roehrl MHA, Wang JV and Wagner G. Discovery of Small-Molecule Inhibitors of the NFAT-Calcineurin Interaction by Competitive High-Throughput Fluorescence Polarization Screening. Biochemistry 200, 43 16067-16075. 

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