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Immunosuppressants

Dr. Fireman is Assistant Professor of Psychiatry, Oregon Health and Science University, Portland, Ore. Dr. DiMartini is Associate Professor of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pa. Dr. Armstrong is the Medical Director, Center for Geriatric Psychiatry, Tuality Forest Grove Hospital, Forest Grove, Ore., and Associate Clinical Professor of Psychiatry, Oregon Health and Science University, Portland, Ore. Dr. Cozza is the staff psychiatrist for the Infectious Disease Service, Department of Medicine, Walter Reed Army Medical Center, Washington, D.C., and Assistant Professor of Psychiatry, Uniformed Services University of Health Sciences, Bethesda, Md. Drs. Armstrong and Cozza are co-authors, along with Dr. Jessica R. Oesterheld, of the Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins, 2nd edition. (American Psychiatric Publishing, Inc., 2003). Address correspondence to Dr. Fireman, Department of Psychiatry, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Portland, OR 97239-3098; firemanm{at}ohsu.edu (e-mail).
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

ABSTRACT

Immunosuppressants are prescribed to prevent rejection of transplanted tissues and organs and are also used in the treatment of autoimmune disorders. Consultation-liaison psychiatrists increasingly encounter patients taking these agents as the number of transplant recipients increases and the indications for the use of immunosuppressants expands. These drugs have potentially deleterious physical, mental, and biochemical side effects. In addition, transplant recipients and patients with autoimmune disorders commonly have comorbid illnesses that require pharmacologic treatment. The management of these patients is challenging secondary to the severity of these illnesses, the number of medications prescribed, and the potential for adverse drug-drug interactions. Knowledge of the pharmacokinetic properties of these drugs and the potential for serious drug-drug interactions that cause alterations in serum levels of the immunosuppressant medications is essential. Increased serum levels may cause serious toxic effects and decreased serum levels may lead to rejection of the transplanted organ or worsening of the autoimmune disorder. Adverse events may also occur when serum levels of medications prescribed for comorbid illnesses are altered by administration of immunosuppressants. The pharmacokinetic drug-drug interaction profiles of the glucocorticoids, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, and monoclonal antibodies are discussed in this review.

The immunosuppressants include those medications commonly used to prevent rejection of transplanted organs as well as agents used in the treatment of autoimmune disorders. Most of these drugs have a narrow therapeutic index and potential for significant toxicities. Furthermore, the immunosuppressants have significant drug-drug interactions when used together as well as significant interactions with agents prescribed to treat the side effects and comorbid illnesses that commonly occur in transplant patients and patients with autoimmune disorders. Antihypertensives, psychotropic medications, antimicrobials, lipid-lowering agents, and anti-ulcer medications are frequently prescribed to patients receiving immunosuppressant medications.^1,2 Drug-drug interactions can significantly increase the deleterious side effects of the immunosuppressants. In addition, these interactions may decrease the serum levels and efficacy of the immunosuppressive agents, resulting in rejection of transplanted organs or worsening of the autoimmune disorder.^1–5 Important pharmacokinetic and pharmacodynamic drug-drug interactions occur when immunosuppressants are prescribed with each other and with other medications. Pharmacokinetic drug interactions are interactions by which one drug affects the absorption, distribution, metabolism, and elimination of the second drug. Pharmacodynamic interactions refer to the effect of one drug on the activity of the second drug at the target receptor site or end organ.⁶ The pharmacokinetic drug-drug interaction profiles of the glucocorticoids, cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate, and monoclonal antibodies are discussed in this review. Detailed discussion of the pharmacodynamic drug-drug interactions that may occur with these agents is beyond the scope of this paper. However, the clinician should be aware that pharmacodynamic interactions involving these medications may result in significant adverse effects as well.¹

P-glycoprotein is a large membrane-bound transport protein which appears responsible for the transport of various substrates across cell membranes. P-glycoprotein functions as a "pump," preventing drugs from penetrating the cell and removing drugs from within the cytoplasm to the extracellular medium. P-glycoproteins are found in many sites, including the jejunum and the blood-brain barrier. The location and the function of P-glycoprotein have a major impact on the bioavailability of many drugs. The cytochrome P450 3A4 enzyme and P-glycoprotein appear to play major roles in the pharmacokinetics of the immunosuppressant medications as well as many other medications in clinical use. Therefore, it is not surprising that a large number of drug-drug interactions involving this class of agents have been reported and an even greater number have been postulated as potential interactions (Table 1 and Table 2). Many of these agents are both substrates and inhibitors of 3A4 and P-glycoprotein. An interrelationship between 3A4 and P-glycoprotein may exist, as the list of substrates, inhibitors, and inducers of 3A4 is similar to the list of substrates, inhibitors, and inducers of P-glycoprotein.^2–4,7

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TABLE 1. Immunosuppressant Pharmacokinetic Interactions

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TABLE 2. Immunosuppressant Pharmacokinetic Interactions

SPECIFIC IMMUNOSUPRESSANT AGENTS

Glucocorticoids
Glucocorticoids, particularly prednisone, have historically been used as part of immunosuppressive protocols in transplant patients. Although recent studies have shown that doses can be reduced and even discontinued in the long-term treatment of these patients, high doses of these agents continue to be important in preventing graft rejection in the immediate posttransplant period and in the treatment of acute rejection.⁸ These medications have multiple adverse effects, including adrenal suppression, glucose intolerance, hyperlipidemia, osteoporosis, cataracts, depression, and psychosis.^5,9 Prednisone is a pro-drug and must be metabolized to prednisolone, the clinically active agent. The glucocorticoids are metabolized by the cytochrome P450 3A4 enzyme and are believed to be inducers of 3A4 as well. Ketoconazole and diltiazem, both 3A4 inhibitors, have been observed to increase levels of prednisone and prednisolone, thereby increasing the toxic effects of these agents.^4,10 Phenobarbital, phenytoin, and rifampin are potent inducers of 3A4 and may enhance glucocorticoid metabolism. This may cause decreased levels of prednisone and prednisolone, which may result in transplant rejection, symptoms of adrenocortical insufficiency, and decreased survival.^1,9

Cyclosporine
Cyclosporine (Sandimmune®, Gengraf®, Neoral®), a lipopholic 11 amino-acid polypeptide isolated from a fungus, is an effective immunosuppressive agent that has been used in clinical practice since the early 1980s. Cyclosporine exerts its immunosuppressive action by interfering with the activation and proliferation of cytotoxic T cells.^4,9 Cyclosporine has a narrow therapeutic index, and many drug-drug interactions have been described that may result in either toxic or subtherapeutic cyclosporine levels. Elevated cyclosporine levels may cause nephrotoxicity and neurotoxicity while subtherapeutic levels may cause rejection of the transplanted organ.

Cyclosporine absorption after oral administration is affected by both P-glycoprotein and 3A4 activity in the bowel. P-glycoprotein is responsible for clearing cyclosporine from cells into the intestinal lumen, and cyclosporine is metabolized via 3A4 intestinal activity. Hepatic metabolism of cyclosporine is also mediated by 3A4. Both inhibitors and inducers of 3A4 and P-glycoprotein may alter cyclosporine levels. Cyclosporine itself is an inhibitor of 3A4 and P-glycoprotein and may affect levels of drugs dependent upon these for their metabolism.^3,4

Most inhibitors of 3A4 may significantly increase cyclosporine levels and clinically significant drug-drug interactions have been described with many of these agents. Ketoconazole, fluconazole, itraconazole, myconazole, clarithromycin, erythromycin, fluvoxamine, nefazodone, sertraline, verapamil, diltiazem, allopurinol, atorvastatin, simvastatin, losartan, and grapefruit juice are all thought to increase cyclosporine levels via inhibition of 3A4.^{1–5,8,11–17} Depression is a frequent complication of organ transplantation; prescription of antidepressant medication is often necessary. The SSRIs and other newer antidepressants are generally thought to be safe and effective when used in medically ill patients. However, several cases of cyclosporine toxicity have been reported in transplant patients prescribed nefazodone or fluvoxamine for depression.^11,13 In one case there was a 10-fold increase in the cyclosporine level. Both these medications are potent inhibitors of 3A4 and presumably the metabolism of cyclosporine.¹¹

P-glycoprotein inhibitors may also alter cyclosporine levels. It has been postulated that P-glycoprotein inhibition by digoxin decreases the first pass metabolism of cyclosporine, thereby increasing cyclosporine levels. Acyclovir, valsartan, and alendronate also appear to decrease the clearance of cyclosporine; the exact mechanism of the pharmacokinetic interactions with these medications remains unclear.¹⁴

Carbamazepine, phenobarbital, phenytoin, rifampin, modafanil, sulfinpyrazone, and St. John’s wort are all inducers of 3A4 or P-glycoprotein. All have been reported to decrease levels of cyclosporine.^{1,3–5–12,18} St. John’s wort is a popular herbal remedy for mild depression, and often patients view it as "safer" than prescribed antidepressants. There have been at least 12 cases reported of transplant rejection secondary to decreased cyclosporine levels in patients using St. John’s wort for treatment of depression. In two case series cyclosporine levels decreased an average of close to 50% after administration of St. John’s wort.^{3,4,8,19–21} Ticlopidine also decreases cyclosporine levels, however the mechanism remains to be elucidated.³

A few clinically significant alterations in levels of other drugs when given concomitantly with cyclosporine have been noted. Cyclosporine may increase digoxin levels through alteration of renal clearance of digoxin.¹⁷ Levels of HMG-CoA reductase inhibitors, used to treat hyperlipidemia, such as lovastatin and simvastatin may be increased by cyclosporine inhibition of 3A4. Several cases in the literature describe rhabdomyolysis presumed to be secondary to high levels of statin drugs when these drugs were given in combination with cyclosporine.^12,17

The number and potential clinical significance of the above drug interactions point to the necessity for careful monitoring of cyclosporine levels when drugs known to affect 3A4 and P-glycoprotein are added or deleted from a patient’s regimen. In addition, use of drugs whose metabolism may be altered by cyclosporine should be carefully monitored to avoid toxicities.

Tacrolimus
Tacrolimus (FK-506, Prograf®) is a macrolide immunosuppressant with a mechanism of action similar to that of cyclosporine. The major adverse effects associated with tacrolimus include nephrotoxicity, neurotoxicity, diabetes mellitus, hypertension, and gastrointestinal upset. Tacrolimus has a narrow therapeutic index. Levels above the therapeutic range are associated with increased adverse effects, particularly neurotoxicity and nephrotoxicity. Low levels of tacrolimus are associated with an increased incidence of rejection.²²

Tacrolimus is a substrate of 3A4 and P-glycoprotein and may be a substrate of uridine 5'-diphosphate glucuronyltransferase (UGT).^3,4 Many known inhibitors of 3A4 have been reported to increase tacrolimus levels. These include clarithromycin, diltiazem, erythromycin, fluconazole, indinavir, itraconazole, ketoconazole, nefazodone, ritonavir, clotrimazole, felodipine, and grapefruit juice.^{3,4,16,22–28} Other known inhibitors of 3A4 are also likely to increase tacrolimus levels. Campo et al. reported a case of a depressed adolescent kidney transplant recipient who was treated for 4 weeks with 150 mg/day of nefazodone. The patient was noted to have an increase in serum creatinine from 1.2 to 2.4 mg/dl and a serum tacrolimus level in the toxic range.²⁹ Although not reported, inhibitors of P-glycoprotein such as quinidine, calcium channel blockers, azole antifungals, protease inhibitors, and cancer chemotherapeutics (e.g., vinblastine) could similarly be expected to increase tacrolimus levels.²² Inducers of 3A4 and P-glycoprotein, such as rifampin, phenytoin, phenobarbital, and St. John’s wort have been shown to decrease tacrolimus levels.^4,22–24 Tacrolimus is an inhibitor of 3A4 and has been shown, in vitro, to affect concentrations of drugs metabolized by 3A4.^3,4,22,23,30 Kotanko et al. reported one case of tacrolimus-induced elevation of simvastatin levels leading to rhabdomyolysis and renal failure.³¹

Tacrolimus appears to be both an inhibitor and substrate of the UGT enzymes. Gornet et al. reported that coadminstration of tacrolimus and irinotecan (an anticancer drug) to a patient receiving chemotherapy after liver transplant resulted in increased toxicity of the latter agent. They proposed that inhibition of UGT1A1 by tacrolimus interfered with the metabolism of irinotecan.³²

Monitoring of drug levels of tacrolimus appears essential to avoid toxicity and transplant rejection. In addition to the known interactions, a wide variety of medications, herbs, and foods may interact with tacrolimus through the mechanisms outlined above.

Sirolimus
Sirolimus (Rapamycin, Rapamune®) is a macrolide immunosuppressant that blocks T-cell activation by a different mechanism than tacrolimus and cyclosporine. It was introduced clinically in 1999. Adverse effects include hyperlipidemia and bone marrow suppression; it does not appear to cause the neurotoxicity and nephrotoxicity seen with tacrolimus and cyclosporine.^5,9,33 Sirolimus is extensively metabolized via 3A4 and is a substrate of P-glycoprotein.⁴ To date, there are few reports in the literature with regard to drug-drug interactions involving sirolimus. Cyclosporine, diltiazem, ketoconazole, and atorvastatin (all inhibitors of 3A4) have been reported to increase sirolimus levels.^3,4,33–35 Inducers of 3A4, including rifampin, carbamazepine, phenobarbital, and phenytoin can decrease sirolimus levels. It is suspected that many of the known inducers and inhibitors of 3A4 will have significant affects on sirolimus concentrations and that sirolimus levels should be closely monitored when used with any of these agents.^3,4

Mycophenolate Mofetil
Mycophenolate mofetil (CellCept®) interferes with DNA replication by inhibiting inosine monophosphate dehydrogenase, an enzyme necessary for the synthesis of the nucleotide guanine. Mycophenolate mofetil exerts its immunosuppressive effect by interfering with lymphocyte proliferation. Bone marrow suppression and gastrointestinal symptoms are the principal side effects.⁵ Mycophenolate mofetil is rapidly hydrolyzed after absorption to the active drug, mycophenolic acid. The major pathway of mycophenolic acid metabolism is via glucuronidation.⁴ It has been observed that levels of mycophenolic acid (the active agent) in immunosuppressive regimens combining tacrolimus and mycophenolate mofetil are higher than in regimens combining cyclosporine and mycophenolate mofetil. This led to the hypothesis that tacrolimus inhibited the glucuronidation of mycophenolic acid. Subsequent studies have concluded that interaction between cyclosporine and mycophenolic acid actually decreases mycophenolic acid levels. The nature of the interaction between tacrolimus and mycophenolic acid remains unclear.^36–38 There is little known about pharmacokinetic interactions between mycophenolate mofetil and other drugs.

Azathioprine
Azathioprine (Imuran) is a purine analog released for use in the United States in 1968. It has been used widely as an immunosuppressant in both organ transplantation and in the treatment of autoimmune disorders. Azathioprine interferes with DNA and RNA synthesis and exerts its autoimmune action by inhibiting the differentiation and proliferation of T and B lymphocytes. The principle adverse effects of azathioprine are bone marrow suppression and hepatotoxicity.^4,5,9 It is not used as widely today in organ transplantation because of the availability of alternative agents. Azathioprine is a pro-drug and is metabolized to mercaptopurine, the active drug in the liver. The mechanism by which this takes place remains to be elucidated. Mercaptopurine may be excreted unchanged but is also metabolized by thiopurine methyltransferase (TPMT). TPMT is polymorphic, and approximately one in 300 individuals lack TPMT. If normal doses of azathioprine (or mercaptopurine) are administered to patients lacking TPMT, severe toxicity, including myelosuppression, may occur. The current standard of practice includes genetic screening for presence of TPMT prior to prescription of azathioprine.^4,39

Only a few drug-drug interactions involving azathioprine have been reported to date. There have been at least four reports of a drug-drug interaction between azathioprine and warfarin. When these drugs are coadministered, increased doses of warfarin are required for therapeutic anticoagulation.⁴⁰ The combination of azathioprine and allopurinol is known to cause leukopenia, complicating the treatment of hyperuricemia in patients receiving azathioprine.⁴¹ The exact mechanism of these drug-drug interactions remains unclear.

Monoclonal Antibodies
Monoclonal antibodies are antibodies that are active against a single target antigen. Basiliximab, daclizumab, and muromonab-CD3 (Orthoclone OKT3®) are currently used as adjunctive immunosuppressive agents in organ transplant recipients. Muromonab-CD3 is a murine monoclonal antibody that blocks the function of T cells by reacting with the T cell receptor-CD3 complex found on the surface of circulating human T cells. Muromonab-CD3 is recognized as a foreign protein by the human immune system, and severe adverse reactions can occur. Basiliximab (Simulect®) and daclizumab (Zenapax) were developed by replacing most of the murine portion of the antibody with human amino acid sequences. They are interleukin-2 receptor antagonists that directly inhibit T-cell activation and proliferation. Basiliximab and daclizumab appear to be well tolerated.^4,9,42,43 Relatively few drug-drug interactions have been reported with these agents. Vasquez et al.⁴⁴ reported that muromonab-CD3 increased cyclosporine levels in renal transplant recipients. They postulated that muromonab-CD3 inhibited cyclosporine metabolism by cytokine-induced inhibition of the P450 system. This group of researchers also reported a significant drug interaction between basiliximab and tacrolimus resulting in increased tacrolimus blood levels when these drugs are administered together. Although the mechanism for this interaction is unproven, they postulated that cytokine-induced inhibition of 3A4 may also be responsible.⁴⁵ Strehlau et al. noted similar elevations in cyclosporine levels when basiliximab was used concurrently and postulated that inhibition of 3A4 by basiliximab was also responsible.⁴⁶

PHARMACODYNAMIC INTERACTIONS

Cyclosporine and tacrolimus are nephrotoxic and may increase the nephrotoxicity of other agents, including aminoglycosides, vancomycin, and amphotericin. Increased neurotoxicity and nephrotoxicity may be seen when either cyclosporine or tacrolimus is used in combination with acyclovir or ganciclovir. Concomitant use of cyclosporine or tacrolimus with nonsteroidal anti-inflammatory agents has been reported to cause hypertension, edema, and nephrotoxicity. An increased risk of gingival hyperplasia has been noted when cyclosporine is used in combination with nifedipine and phenytoin.¹ Discussion of all of the clinically significant pharmacodynamic interactions with the immunosuppressants is beyond the scope of this paper, but the clinician should be aware of the potential severity of these interactions.

SUMMARY

The immunosuppressants are agents used to prevent rejection in organ transplant recipients and for the treatment of autoimmune disorders. These drugs are often used in combination with each other and are commonly part of a multidrug regimen. Antimicrobials, antihypertensives, psychotropic medications, lipid-lowering agents, H-2 blockers, and proton-pump inhibitors are frequently prescribed to patients receiving immunosuppressants. Most immunosuppressants have a narrow therapeutic index as well as significant toxicities. Both sub- and supratherapeutic levels of these agents may cause significant morbidity and mortality. Immunosuppressants may alter the pharmacokinetics of other medications resulting in either elevated or subtherapeutic serum levels of those agents. The cytochrome P450 3A4 enzyme and P-glycoprotein play important roles in the metabolism of a number of these agents. 3A4 is responsible, at least in part, for the metabolism of the majority of the drugs on the market. In addition, a variety of agents, including the immunosuppressants, may inhibit or induce 3A4. Clinicians involved in the care of patients receiving immunosuppressants must be aware of the potential for pharmacokinetic drug-drug interactions whenever medications are added or deleted from a patient’s regimen. Psychiatrists involved in the care of these patients must be aware of the potential neurotoxicity of drug-drug interactions involving immunosuppressants that may cause psychiatric symptoms. When prescription of psychotropic medication is necessary, use of medications with fewer effects on 3A4 and P-glycoprotein should be considered. Close monitoring of serum levels, other appropriate laboratory studies, and clinical assessment of side effects is essential. The clinician should be aware of the existence of therapeutic serum levels and how serum levels are measured in their patient population. Genetic heterogeneity and issues of patient compliance may also complicate the management of these patients. Drug-drug interactions involving immunosuppressants are potentially serious but may be avoided by awareness of the potential interactions and careful clinical monitoring.

REFERENCES

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