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

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

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 recom-

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

troglitazone or rosiglitazone and during switching to other antihyperglycemic agent.

424 Organ Donation and Transplantation - Current Status and Future Challenges

*4.2.5. Psychiatric medication*

mended to avoid metabolic drug interactions.

*4.2.6. Treatment of hyperuricemia*

[142–144].

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

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 transplant patients during immunosuppressive therapy.
