**4.2. Metabolic drug interactions between immunosuppressants and post-transplant medication**

#### *4.2.1. Treatment and prevention of infections*

Environmental circumstances and immune deficiencies due to immunosuppression therapy make recipients susceptible for infections that are one of the leading complications after organ transplantation; therefore, prevention and management of infections is a major task primarily in the early postoperative period. Since fungal infections are a threatening cause of morbidity and mortality, the antifungal prophylaxis is an important element of posttransplant medication. The antifungal azole-derivatives are potent (some of them are very strong) CYP3A inhibitors, predicting potential metabolic drug interactions with calcineurin inhibitors, mTOR inhibitors, or corticosteroids. The most potent CYP3A inhibitor is ketoconazole, able to increase blood concentrations (AUC) of ciclosporin (> 4-fold), tacrolimus (> 2-fold), sirolimus (11-fold), everolimus (15-fold), and methylprednisolone (> 2-fold) [73, 74]. Because of the substantial increase in blood concentrations of several immunosuppressants that can be avoided by drastic reduction of immunosuppressant doses and because of other adverse effects of ketoconazole, the concomitant medication is discouraged. Fluconazole, itraconazole, and voriconazole are alternative regimens for antifungal therapy or prophylaxis; however, all three drugs are azole derivatives and have the capability to inhibit CYP3A function, albeit at a lower extent than ketoconazole [75–77]. Although the continuous immunosuppressant monitoring is highly recommended and dose adjustment (reduction) is generally required, the antifungal treatment with fluconazole, itraconazole, or voriconazole can be safely applied except for voriconazole-sirolimus combination [78]. Because of an extreme (7-fold) increase of sirolimus blood concentrations as a consequence of concomitant use of voriconazole, this combination is contraindicated. Amphotericin B, the nonazole type antifungal agent, does not influence CYP activities; therefore, no metabolic drug interactions can be expected in concomitant treatment with immunosuppressants. However, the widespread use of amphotericin B is limited because of its toxicity profile, primarily because its nephrotoxic side-effect can contribute to the renal injury by ciclosporin or tacrolimus.

Organ transplant patients are at high risk for developing bacterial infections that occur in 20–40% of transplants. Potential sources of infection are from hospital and community exposures, as well as from endogenous flora of patients. Among the antibiotics used for treatment of infections, the macrolide erythromycin and clarithromycin have been reported to interact with immunosuppressive agents. These macrolides are CYP3A substrates and bind to CYP3A4 enzymes, leading to a complex formation that completely inactivates CYP3A4 enzyme [79–82]. The *in vitro* findings were confirmed by clinical observations that blood concentrations of ciclosporin/tacrolimus or sirolimus/everolimus increased as a consequences of concomitant treatment with erythromycin or clarithromycin [73, 83–86]. Page et al. [87] and Mori et al. [88] have reported some potential of azithromycin for drug interaction with ciclosporin and tacrolimus; however, *in vitro* experiments demonstrated that azithromycin poorly interfere with CYP3A4 [89]. When concomitant therapy with these macrolides is necessary, blood concentrations of calcineurin inhibitors or mTOR inhibitors should be carefully monitored, and the immunosuppressant doses should be adjusted. In contrast, the macrolide rifampicin is a potent CYP3A4 inducer and can activate PXR, resulting in a substantial increase in CYP3A4 expression [90]. The increased CYP3A4 activity consequently enhances the metabolism and elimination of calcineurin inhibitors, mTOR inhibitors, and corticosteroids [91–93]. However, blood concentration–guided dose-adjustment of immunosuppressants should be applied carefully because increased metabolism can evoke elevation of toxic metabolite formation (e.g., ciclosporin).

adjustment [68]. Interestingly, CYP3A5 nonexpressers with *CYP3A5\*3/\*3* genotype are more susceptible to glucocorticoid induction than *CYP3A5\*1* carriers [69]; thus, more pronounced increase in tacrolimus exposure can be expected in CYP3A5 nonexpressers after glucocorticoid

ganciclovir, valganciclovir Mycophenolate-glucuronide inhibits renal tubular

Inhibition of CYP3A4

rifampicin CYP3A4 induction; enhanced metabolism of corticosteroids

ritonavir Irreversible inhibition of CYP3A4; increased blood levels of corticosteroids

secretion of ganciclovir; increased blood levels of ganciclovir and increased risk of toxicity (nephrotoxicity, neutropenia, leukopenia)

Increased blood levels of corticosteroids

Clinically significant interaction between mycophenolic acid, the active metabolite of mycophenolate mofetil, and ciclosporin has been reported [70]. The mycophenolate-glucuronide metabolite eliminated into bile undergoes enterohepatic cycling because of intestinal bacterial metabolism and reabsorption of mycophenolic acid. The enterohepatic circulation, contributing to overall pharmacokinetics of mycophenolic acid by 37% in human, is inhibited by concomitant administration of ciclosporin but does not interfere with tacrolimus or sirolimus [71, 72]. In ciclosporin-mycophenolate combination therapy, the reduced blood concentration of mycophenolic acid is necessary to ameliorate by increasing dose of mycophenolate mofetil. Furthermore, special attention on optimal dosing is required during switching ciclosporin-

**4.2. Metabolic drug interactions between immunosuppressants and post-transplant** 

Environmental circumstances and immune deficiencies due to immunosuppression therapy make recipients susceptible for infections that are one of the leading complications after organ transplantation; therefore, prevention and management of infections is a major task

mycophenolate to tacrolimus-mycophenolate therapy and *vice versa*.

**Immunosuppressant Drug interactions Consequences** *Antiviral agents*:

420 Organ Donation and Transplantation - Current Status and Future Challenges

*Antifungals*:

*Antibiotics*:

*Antiviral agents*:

ketoconazole, fluconazole, voriconazole, itraconazole

**Table 2.** Clinically relevant pharmacokinetic drug interactions with immunosuppressants.

withdrawal.

Prednisolone Methylprednisolone

**medication**

*4.2.1. Treatment and prevention of infections*

A significant cause of graft failure still remains viral infections, which are acquired as new infection or reactivation of latent viruses. After transplantation, cytomegalovirus (CMV) is the most common viral infection in recipients, primarily in those CMV-seronegative patients who were transplanted with graft from CMV-seropositive donors, resulting in viral reactivation. For prophylaxis and treatment of CMV infection, aciclovir, ganciclovir, and valganciclovir (the prodrug of ganciclovir) are generally applied. None of these antiviral drugs influences the function of drug-metabolizing CYPs or UDP-glucuronyl transferases, and consequently, they do not modify the pharmacokinetic properties of immunosuppressants. Aciclovir and ganciclovir are eliminated primarily in the urine as unchanged compounds. Increased risk of nephrotoxicity and leukopenia has been reported in patients who were co-medicated with a drug that can reduce renal clearance of aciclovir or ganciclovir. During co-administration with mycophenolate or mycophenolate-mofetil, mycophenolate-glucuronide and aciclovir or ganciclovir can significantly compete for renal tubular secretion, resulting in an increase in aciclovir/ganciclovir and mycophenolate-glucuronide exposure, as well as the risk of nephrotoxicity or leukopenia [94–96]. Management of potent metabolic drug interactions between antiviral protease inhibitors and immunosuppressants is a major challenge because most of the protease inhibitors are clinically significant CYP3A4 inhibitors. Ritonavir-boosted therapies require substantial reduction of immunosuppressant doses (to 5–20% for ciclosporin; to 1–3.5% for tacrolimus) with continuous monitoring of blood concentrations [97–101].

frequent monitoring of immunosuppressant blood concentrations. The metabolism of all three Ca-channel blockers is primarily catalyzed by CYP3A4, anticipating potential drug interactions with immunosuppressants. Furthermore, significant inhibition of CYP3A4 by diltiazem, verapamil, and amlodipine has been demonstrated with an additional inhibitory property of metabolite intermediate complex formation that catalytically inactivates CYP3A4 and CYP3A5 enzymes [79, 80, 82, 110–114]. The inactivation of CYP3A enzymes by comedication with these antihypertensive drugs consequently leads to a permanent increase in blood concentrations of calcineurin inhibitors or mTOR inhibitors [115–122]. In transplant recipients comedicated with sirolimus and verapamil, an increase of blood concentrations of both sirolimus and verapamil was observed [123]. Furthermore, in patients carrying wild-type *CYP3A5\*1* allele, concomitant treatment with amlodipine significantly decreased tacrolimus clearance, and along with the changes in tacrolimus pharmacokinetics, an increase in amlodipine blood concentrations was also observed [124]. The metabolism of the Ca-channel blocker nifedipine is catalyzed almost exclusively by CYP3A enzymes, and competition for the active site of CYP3As may be expected if nifedipine and CYP3A substrate calcineurine inhibitors or mTOR inhibitors are concomitantly applied. In contrast, no evidence for pharmacokinetic drug interactions has been provided in transplant recipients treated with nifedipine and ciclosporin/tacrolimus or sirolimus/ everolimus. Carvedilol is often used for treatment of hypertension in transplant patients, and pharmacokinetic drug interaction between carvedilol and ciclosporin has been observed that required 10–20% reduction of ciclosporin doses to maintain the blood concentrations within the therapeutic range [125, 126]. The major metabolic pathways of carvedilol are catalyzed by CYP2D6 and CYP1A2 rather than by CYP3A4 [127]; however, inhibition of CYP3A enzymes by carvedilol does not account for pharmacokinetic drug interaction with ciclosporin. Carvedilol has been demonstrated to block the function of the ABCB1 transporter protein (ATP-binding cassette B1; previously called as Pgp) [128]. In the intestinal wall, ABCB1 transporter pumps pharmacons or other xenobiotics passed into the enterocytes back into the gut lumen. The inhibition of ABCB1-mediated transcellular transport in the intestine by carvedilol is responsible for the increased absorption of ciclosporin. Under careful monitoring of ciclosporin blood concentration, the ABCB1 inhibition by carvedilol can be beneficial in ciclosporin-sparing therapy for transplant patients. Since the absorption of tacrolimus and mTOR inhibitors is also mediated by ABCB1, similar pharmacokinetic drug interactions between these immunosuppres-

Metabolic Drug Interactions with Immunosuppressants http://dx.doi.org/10.5772/intechopen.74524 423

sants and carvedilol are presumably developed as with ciclosporin.

Hyperglycemia developing posttransplant diabetes mellitus is generally medication related. Corticosteroids can evoke reduction of glucose tolerance, whereas ciclosporin and tacrolimus directly block insulin-release by islet cells. The metabolism of the sulfonylurea type antidiabetic agents (e.g., tolbutamide, glipizide, glibenclamide, and glimepiride) is mediated by CYP2C9; therefore, metabolic drug interactions with immunosuppressants are not expected in patients treated with any of these oral hypoglycemic drugs. Although the thiazolidinedione type troglitazone and rosiglitazone are not CYP3A substrates, they can induce the expression of CYP3A enzymes by activation of the nuclear receptors, PXR and CAR [129–132]. Enhanced transcription results in an increase in CYP3A activities and the metabolism of calcineurin inhibitors,

*4.2.4. Antihyperglycemic therapy*
