*4.2.2. Treatment of dyslipidemia*

Dyslipidemia is often developed as an adverse impact of immunosuppressive therapy [102]. Ciclosporin, mTOR inhibitors, and prednisone are mainly implicated in lipid alterations. For treatment of hypercholesterolemia, the basic guidelines for dyslipidemia recommend diet and HMG-CoA reductase (hydroxymethyl-glutaryl-CoA reductase) inhibitor statins with special considerations for transplant patients. Although both ciclosporin and most statins (atorvastatin, fluvastatin, simvastatin, lovastatin) are primarily metabolized by CYP3A4 and metabolic drug interactions are likely occur, statins do not evoke increased ciclosporin exposure [103–106]. In contrast, ciclosporin induces significant elevation of statin blood concentrations which can be explained by the ten-fold higher molar concentrations of ciclosporin than statins. In combination with ciclosporin, the blood levels are increased in a statin-dependent manner, e.g., lovastatin is increased to a much greater extent than atorvastatin [104, 107]. Dose reduction of lipid-lowering agents is recommended to avoid myopathy or rhabdomyolysis. The blood concentrations of macrolide immunosuppressants (tacrolimus, sirolimus, and everolimus) are similar to that of statins [108, 109]; therefore, the lack of clinically relevant interactions between macrolides and statins is not unexpected.

#### *4.2.3. Antihypertensive agents*

Organ transplantation and immunosuppressive therapy (e.g., ciclosporin, prednisone) frequently trigger hypertension or worsen the preexisting disease in patients. While most of the antihypertensive agents (β-adrenoceptor blockers, α1-adrenergic receptor antagonists, central α2-adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) are not expected to influence the pharmacokinetics of immunosuppressants, medication with diltiazem, verapamil, or amlodipine requires special consideration and 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 immunosuppressants and carvedilol are presumably developed as with ciclosporin.

#### *4.2.4. Antihyperglycemic therapy*

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

422 Organ Donation and Transplantation - Current Status and Future Challenges

1–3.5% for tacrolimus) with continuous monitoring of blood concentrations [97–101].

interactions between macrolides and statins is not unexpected.

Dyslipidemia is often developed as an adverse impact of immunosuppressive therapy [102]. Ciclosporin, mTOR inhibitors, and prednisone are mainly implicated in lipid alterations. For treatment of hypercholesterolemia, the basic guidelines for dyslipidemia recommend diet and HMG-CoA reductase (hydroxymethyl-glutaryl-CoA reductase) inhibitor statins with special considerations for transplant patients. Although both ciclosporin and most statins (atorvastatin, fluvastatin, simvastatin, lovastatin) are primarily metabolized by CYP3A4 and metabolic drug interactions are likely occur, statins do not evoke increased ciclosporin exposure [103–106]. In contrast, ciclosporin induces significant elevation of statin blood concentrations which can be explained by the ten-fold higher molar concentrations of ciclosporin than statins. In combination with ciclosporin, the blood levels are increased in a statin-dependent manner, e.g., lovastatin is increased to a much greater extent than atorvastatin [104, 107]. Dose reduction of lipid-lowering agents is recommended to avoid myopathy or rhabdomyolysis. The blood concentrations of macrolide immunosuppressants (tacrolimus, sirolimus, and everolimus) are similar to that of statins [108, 109]; therefore, the lack of clinically relevant

Organ transplantation and immunosuppressive therapy (e.g., ciclosporin, prednisone) frequently trigger hypertension or worsen the preexisting disease in patients. While most of the antihypertensive agents (β-adrenoceptor blockers, α1-adrenergic receptor antagonists, central α2-adrenergic receptor agonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers) are not expected to influence the pharmacokinetics of immunosuppressants, medication with diltiazem, verapamil, or amlodipine requires special consideration and

*4.2.2. Treatment of dyslipidemia*

*4.2.3. Antihypertensive agents*

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, mTOR inhibitors and corticosteroids, increasing the risk of rejection [133]. Immunosuppressant dose adjustment is required to avoid subtherapeutic blood concentrations, and careful monitoring of immunosuppressant blood concentrations is recommended during withdrawal of troglitazone or rosiglitazone and during switching to other antihyperglycemic agent.

**4.3. Metabolic drug interactions between immunosuppressants and herb** 

potential of St John's wort that can endanger the success of organ transplantation.

plant patients during immunosuppressive therapy.

**5. Concluding remarks**

Concomitant intake of grapefruit (*Citrus paradisii*) or pomelo (*Citrus grandis*) has been demonstrated to increase the bioavailability of immunosuppressants [147, 160, 161]. Some components of these citrus fruits, bergamottin and naringenin responsible for the bitter taste, can inhibit the activities of CYP3A4 and CYP3A5 enzymes both in the intestinal wall and in the liver, resulting in significant reduction of first-pass metabolism of CYP3A substrates, including ciclosporin and tacrolimus [162–164]. Significant reduction of ciclosporin/tacrolimus doses is necessary to avoid the risk of nephrotoxicity or other adverse events associated with immunosuppressive therapy. The furanocoumarin bergamottin is a "suicide substrate," namely it is metabolized by CYP3A4 to an epoxid metabolite that covalently binds to and inactivates the enzyme [165]. The flavonoid naringenin was found to be a less-potent CYP3A4 inhibitor than bergamottin [166]; however, during consumption of grapefruit, the inhibitory effects of naringenin and bergamottin are added together. Since clear evidence of bergamottin content and CYP3A4 inhibitory potential of citruses other than grapefruit and pomelo was provided [167], the transplantation centers do not recommend citrus consumption for trans-

Although success of organ transplantation is continuously improving, several short- and long-term complications can adversely affect the outcome. One of the most significant factors influencing the long-term graft and patient survival is the appropriate immunosuppressive

Pharmacokinetic herb-drug interactions can also significantly influence the outcome of immunosuppressive therapy and long-term graft survival [145]. St John's wort (*Hypericum perforatum*) extract and grapefruit juice are well described as modifiers of pharmacokinetic properties of ciclosporin and tacrolimus [146–148]. St John's wort extract is a herbal product for treatment of symptoms of mild or moderate depression, including anxiety, fatigue, and sleeping problems. The extract contains a number of biologically active components, e.g., hyperforin of high interest. Hyperforin has a strong affinity for PXR and significantly increases the expression and activities of CYP3A4 enzyme, which is involved in metabolism of many drugs [149, 150]. Consequently, chronic consumption of St John's wort extract can decrease the blood concentrations of CYP3A substrates, such as calcineurin inhibitors, mTOR inhibitors, and corticosteroids [151–154]. In addition, St John's wort extract has been reported to induce the expression of ABCB1 transporter that reduces the absorption of ABCB1-ligand drugs from the gut. The hyperforin contents of commercially available St John's wort preparations are variables that appear to significantly affect the extent of pharmacokinetic interactions [150, 155]. Coadministration of ciclosporin with St John's wort extract has been reported to lead a 40–60% decrease of ciclosporin blood concentrations, increasing the risk of rejection; therefore, substantial dose adjustment is required [151, 152, 155–159]. Since clinicians are often unaware of concomitant consumption of herbal supplements, transplant patients should be informed about the drug interaction

Metabolic Drug Interactions with Immunosuppressants http://dx.doi.org/10.5772/intechopen.74524 425

**components**

#### *4.2.5. Psychiatric medication*

The most common psychiatric disorders encountered in transplant patients are anxiety, depression, mood disorders, behavior problems, and insomnia that are reversible in most cases; however, they often require psychotherapy with antidepressants, mood stabilizers, anxiolytic agents, or even with antipsychotics. Many of these pharmacons are metabolized by enzymes other than CYP3A4 and do not influence the drug-metabolizing activities of CYP3A4; consequently, metabolic drug interactions with immunosuppressants cannot be expected. Nevertheless, the CYP3A4 inducing or inhibitory properties of some of these psychopharmacons should be considered. The mood stabilizer carbamazepine and valproic acid have been clearly evidenced to be able to activate CAR and PXR. The nuclear receptor activation leads to an increase in transcription of *CYP3A4* gene and CYP3A4 metabolic activity [134, 135], anticipating decrease of immunosuppressant blood concentrations [136]. To reduce the risk of organ rejection, adjustment (increase) of immunosuppressant doses is required with continuous monitoring of immunosuppressant blood levels. Furthermore, the CYP3A4 deinduction process can last for about 2 weeks after cessation of carbamazepine or valproic acid [137]; thus, careful monitoring of immunosuppressant blood concentrations during withdrawal is essential. The comedication with the antidepressant fluvoxamine is contraindicated because of its strong inhibitory properties for CYP3A4 substrates and potential drug interactions with ciclosporin/tacrolimus or with sirolimus/everolimus [80, 138, 139]. For psychotherapeutic agents that are CYP3A substrates (haloperidol, quetiapine, clonazepam, midazolam, alprazolam), continuous monitoring of immunosuppressant blood levels is highly recommended to avoid metabolic drug interactions.

#### *4.2.6. Treatment of hyperuricemia*

The metabolic drug interactions with ciclosporin/tacrolimus, sirolimus/everolimus, and corticosteroids are generally associated with reversible or irreversible inhibition of CYP3A activities, as well as with transcriptional induction of CYP3A4 and CYP3A5 expression. Clinically significant drug interaction occurs during simultaneous therapy with azathioprine (or 6-mercaptopurine) and allopurinol, the antihyperuricemic agent [140, 141]; however, it involves enzyme other than CYP3As. The metabolism of both 6-mercaptopurine and allopurinol is catalyzed by xantine oxidase, anticipating metabolic drug interactions and developing serious adverse reactions. As a consequence of inhibition of xantine oxidase by allopurinol, myelotoxicity is evoked by the accumulation of 6-thioguanine-nucleotide metabolites of azathioprine. The risk of bone marrow depletion is increased in patients with low thiopurine methyl-transferase activity. To avoid the serious myelosuppression during treatment of hyperuricemia and gout, substantial reduction of azathioprine dose (by at least 50%) is required when allopurinol is given concomitantly, or alternative agents other than allopurinol should be considered [142–144].
