Metabolic Drug Interactions With Immunosuppressants

DOI: 10.5772/intechopen.
74524
Provisional chapter
Chapter 20
Metabolic Drug Interactions with

Metabolic Drug Interactions with Immunosuppressants
Immunosuppressants
Katalin Monostory
Katalin Monostory
Additional information is available at the end of the chapter
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/intechopen.74524
Abstract
Organ transplantation has become a routine clinical practice for patients with end-
stage disease of liver, kidney, heart, or lung. Although improved immunosuppressant
therapy substantially contributes to the success of transplantation, clinicians continue
to face challenges because of wide interindividual variations in blood concentrations
resulting in subtherapeutic or supratherapeutic levels. Many undesired side-effects or
therapeutic failure of immunosuppressants as a consequence are the results of differ-
ences or changes in drug metabolism. Considering genetic and nongenetic factors, such
as co-medication, can refine the immunosuppressant therapy, facilitating personalized
treatments to individual recipients. This review provides an up-to-date summary of
functional polymorphisms of enzymes involved in the metabolism of immunosuppres-
sants with low molecular weight and of the clinical significance of metabolic drug inter-
actions between immunosuppressive agents and other drugs in therapeutic regimens of
transplant recipients.
Keywords: drug metabolism, genetic polymorphism, phenoconversion, calcineurin

inhibitors, mTOR inhibitors, corticosteroids, inosine monophosphate dehydrogenase
inhibitors
1. Introduction
Many undesired side-effects or therapeutic failures of drugs are the results of differences
or changes in drug metabolism. A patient’s drug metabolizing capacity, highly influenced
by genetic variations or alterations in the expression and activities of drug-metabolizing
enzymes, can substantially modify the pharmacokinetics of a drug and eventually its efficacy
or toxicity [1]. Even if the routine clinical practice applies blood concentration guided dosing,
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410 Organ Donation and Transplantation - Current Status and Future Challenges
the interindividual variability in drug metabolism calls for personalized medication primarily
for drugs with narrow therapeutic index [2, 3]. The identification of genetic and nongenetic
factors that can potentially affect the pharmacokinetics of a particular drug is a prerequisite
of tailored pharmacotherapy [4, 5].
2. Genetic and nongenetic variations of drug-metabolizing

cytochrome P450 (CYP) enzymes
CYP enzymes are the key players in the metabolism of most drugs; therefore, interindividual
and intraindividual variations in CYP activities are of significant importance in clinical practice.
The pharmacokinetic variability can divide the population into poor, intermediate, extensive,
and ultra-rapid metabolizer phenotypes. The loss-of-function mutations in CYP genes result
in permanent poor metabolism, whereas nongenetic (internal or environmental) factors can
substantially modify the expression and activities of CYP enzymes, evoking transient poor or
extensive/ultra-rapid metabolism [6, 7]. The clinical relevance for many CYP genetic variants,
regarding drug efficacy, adverse drug reactions, or dose requirement, has been clearly evi-
denced [6–9]; however, the heritable genetic polymorphisms are not the only determinant fac-
tors in interindividual differences in drug metabolism. CYP genotype determines the potential
for the expression of functional or nonfunctional enzymes; and nongenetic host factors (age,
sex, and disease states) and environmental factors (nutrition, medication, smoking, and alcohol
consumption) can alter the expression and activities of CYP enzymes [10]. Homozygous wild
genotype, predicted to be translated to functional CYP enzyme, can be transiently switched
into poor or extensive metabolizer phenotype, due to phenoconversion [1, 11]. Consequently,
both the CYP genotype and the current CYP expression or activity should be considered for the
estimation of a patient’s drug-metabolizing capacity.
The prevalence of loss-of-function or gain-of-function alleles is generally 1–10%; however, the

distribution of the common CYP variants varies among different ethnic populations. CYP3A
enzymes, responsible for the metabolism of approximately 40% of the drugs on the market,
including many immunosuppressant agents, display great genetic and nongenetic variations.
For CYP3A5, substantial interethnic differences in allelic variants have been demonstrated.
The prevalence of CYP3A5*3 allele (6986A > G), resulting in splicing defect and nonfunctional
CYP3A5 protein, is 88–97% in white (Caucasian), 66% in Asian, and 12–35% in African popu-
lations; consequently, a higher average proportion of functional CYP3A5 in the total hepatic
CYP3A pool is expected in subjects of black origin [7, 12]. On the other hand, the enormous,
even more than 100-fold interindividual variability in the expression and activity of CYP3A4
is attributed to nongenetic factors rather than genetic polymorphisms [13]. CYP3A4*1B allele,
which has a frequency of 3–5% in white populations, but a much higher frequency in African
population (50–82%) has been reported to result in increased transcription; however, the clini-
cal significance of CYP3A4*1B to CYP3A4 function seems to be doubtful [14, 15]. CYP3A4*22
allele with the prevalence of 2.5–8% in white and of 4% in Asian populations displays low
hepatic CYP3A4 expression and results in decreased CYP3A4 activity [16]. Although the associ-
ation between CYP3A4 genotype and pharmacokinetic behavior of CYP3A-substrates has been
extensively studied, no clear phenotype-genotype relationship has been described for CYP3A4.
Metabolic Drug Interactions with Immunosuppressants 411
Beside the genetic polymorphisms, one of the major sources of interindividual or intraindi-
vidual variability in drug metabolism is concomitant medication and co-morbidities, evoking
phenoconversion, notably CYP induction and enzyme inhibition [17]. CYP induction leads to
an increase in the expression and activity of CYP enzymes and contributes to the increased
elimination of drugs metabolized by the particular enzyme. Several pathways involving the
activation of various nuclear receptors (PXR pregnane X receptor, CAR constitutive andro-
stane receptor, and glucocorticoid receptor) have been reported to enhance the transcription
of CYP3A genes and to contribute to the complex regulation of CYP3A enzymes by drugs
such as rifampicin, phenobarbital, carbamazepine, and synthetic or natural steroids [18–21].
Reduced drug concentration as a consequence of CYP3A induction leads to the lack of the
pharmacological effect and drug failure. Phenoconversion converting genotypic extensive
metabolism into phenotypic poor metabolism of drugs may occur during inflammation (ster-
ile or infection-induced inflammation). Elevated release of proinflammatory cytokines (IL-6,
IL-1β, TNF-α) has been associated with downregulation of several drug-metabolizing CYPs,
including CYP3A enzymes. The mechanism of downregulation is the repression of PXR and
CAR that are involved in transcriptional regulation of CYP3A expression [22–26]. As a conse-
quence, transient poor metabolizer phenotype is developed, significantly increasing the risk
of adverse drug reactions and impacting the clinical outcome [1, 27]. Likewise, co-medication
can also give rise to poor metabolism. Several drugs or food components (e.g., bergamot-
tin) are known to inhibit the function of drug-metabolizing CYPs; therefore, the concomitant
treatment with a CYP inhibitor is expected to increase the exposure of those pharmacons
that are metabolized by the particular enzyme. As a consequence of CYP inhibition, the risk
of increased exposure and drug-induced adverse reactions can be anticipated, primarily for
drugs with narrow therapeutic index, such as tacrolimus and ciclosporin.
By recognizing individual differences in drug metabolism, personalized drug therapy
adjusted to the patient’s drug-metabolizing capacity can help to avoid the potential side
effects of drugs. The graft and recipient survival are highly influenced by drug-metabolizing
capacity of the liver, and it is essential to predict potential drug-drug interactions and to tailor
medication at both early and late postoperative periods.
3. Metabolism of immunosuppressants
In recent decades, transplantation (liver, kidney, heart, and lung) has become a routine pro-
cedure for patients with end stage disease. Advances in surgical techniques and postopera-
tive therapy have led to increasing numbers of transplantation and extended survival among
these patients. The final outcome of transplantation and the long-term graft function have
been improved mainly due to the development of potent and specific immunosuppressive
drugs. Immunosuppressants efficiently decrease the risk of rejection, blocking the recipient’s
immune system and protecting the transplanted organ. Because of the narrow therapeutic
indexes and increased risk of adverse drug reactions, it is essential to apply personalized
immunosuppressive therapy adjusted to patient’s drug-metabolizing capacity.
Immunosuppressants are generally classified according to their molecular mode of action;

however, in terms of metabolic drug interactions, two main categories must be distinguished
Immunosuppressant Pharmacology Adverse effects Enzymes

responsible for the
metabolism
Calcineurin inhibitors:
Ciclosporin Selective inhibition of Nephrotoxicity, hepatotoxicity, CYP3A4/5

T-cell dependent immune
Hyperlipidaemia, hypertension,
response:
Tremor, hyperkalaemia,
Calcineurin inhibition,
hypomagnaesemia,
Inhibition of cytokine
Hypertrichosis, gingiva hyperplasia
production
Tacrolimus Selective inhibition of Nephrotoxicity, hypertension, CYP3A4/5

T-cell dependent immune diabetes, cholestasis, diarrhea,
response:
Tremor, hyperkalaemia,
Calcineurin inhibition, hypomagnaesemia
Inhibition of cytokine
production
mTOR inhibitors:
Sirolimus Inhibition of B- and T-cell Thrombocytopenia, anaemia, CYP3A4/5

proliferation leukopenia, lymphocele, pneumonitis
Hyperlipidaemia,
Stomatitis aphtosa, wound-healing
complications
Everolimus Inhibition of B- and T-cell Thrombocytopenia, anaemia, CYP3A4/5

proliferation leukopenia, lymphocele, pneumonia
Hyperlipidaemia, hypertonia,
wound-healing complications
Purine analogues:
Azatioprin Inhibition of purine Bone marrow suppression, Thiopurine

metabolism leukopenia, anaemia, S-methyl-
thrombocytopenia, myeloid transferase,
dysplasia,
Xantine oxidase
Cholestasis, hepatotoxicity
Inosine monophosphate
dehydrogenase inhibitors:
Mycofenolate mofetil Selective inhibition of Vomiting, diarrhea, abdominal pain UDP-glucuronyl

inosine monophosphate transferase,
Mycofenolate muscle weakness,
dehydrogenase,
CYP3A4/5
Anaemia, leucopenia
Inhibition of B- and T-cell
proliferation
Corticosteroids:
Prednisone Inhibition of T-cell Adrenal cortex suppression CYP3A4/5

migration and production
Methyl-prednisolone Hypercholesterolemia, diabetes,
of T-cell lymphokines
hypertension, osteoporosis,
osteonecrosis, cataracta, skin atrophy
Table 1. Immunosuppressants with low molecular weight.

according to their molecular weights (agents with low or high molecular weights). High-
molecular-weight agents, such as polyclonal and monoclonal antibodies (e.g., thymoglobulin,
basiliximab, belatacept), that are not substrates for drug-metabolizing enzymes, are metabolized
in common protein degradation pathways (intracellular catabolism by endosomal-lysosomal
system) [28]; therefore, they are not subjects of metabolic drug interactions and not subjects of
this review. In the metabolism of immunosuppressants with low molecular weight, drug-metab-
olizing CYP enzymes are involved which may entail metabolic drug interactions (Table 1).
3.1. Calcineurin inhibitors
For solid organ transplant recipients, the mainstay of the immunosuppressive regimens is
calcineurin inhibitor (CNI) therapy with ciclosporin or tacrolimus which selectively blocks
several signaling processes, resulting in the inhibition of T-cell activation and proliferation
(Figure 1) [29, 30]. These drugs effectively treat allograft rejection; however, they display large
interindividual variability in their pharmacokinetics, requiring monitoring of blood concen-
trations for optimal safety and therapeutic efficacy.
Ciclosporin A is an 11-amino acid cyclopeptide that blocks the production of IL-2 by inhibi-
tion of calcineurin and, as a consequence, the activation of T-cells (Figure 1) [31]. Ciclosporin
undergoes extensive metabolism by CYP3A enzymes, producing more than 30 metabolites.
The major metabolic pathways are N-demethylation to 4-N-demethyl ciclosporin, hydroxyl-
ation at several positions (1-, 6-, 9-monohydroxy and 1,9- or 6,9-dihydroxy-metabolites), and
oxidation to carboxylic acid [32]. Some of the metabolites (e.g., 1,9-dihydroxy-ciclosporin,
Figure 1. Molecular action of calcineurin inhibitors and corticosteriods. AP-1 activator protein 1, CAR constitutive
androstane receptor, CSA ciclosporin, FKBP tarcolimus binding protein, GR glucocoticoid receptor, IL-2 interleukin 2,
JNK c-Jun N-terminal kinase, MAP3K mitogen-activated protein 3 kinase, MPK-1 mitogen-activated protein kinase 1,
NFAT nuclear factor of activated T-cells, PXR pregnane X receptor, Tacr tacrolimus.
1c9-dihydroxy-ciclosporin, 1-carboxy-ciclosporin) are toxic contributing to the nephrotoxic

and hepatotoxic properties of the parent compound [33, 34]. Consequently, high CYP3A activ-
ity increases the rate of ciclosporin metabolism and decreases the immunosuppressive effect,
which requires dose modification [35]. However, high CYP3A activity also increases the toxic
metabolite formation and the risk of nephrotoxicity and hepatotoxicity. Therefore, immuno-
suppressive strategy must consider the blood concentrations of both ciclosporin and the toxic
metabolites, especially if they are accompanied with symptoms indicating nephrotoxicity or
hepatotoxicity.
Immunosuppressive properties of tacrolimus are similar to ciclosporin; however, for the same
pharmacological effect, significantly lower blood concentration of tacrolimus is required
than that of ciclosporin. Tacrolimus, the 23-membered macrocyclic lactone, is converted by
demethylation, hydroxylation, and ring rearrangement to at least 15 metabolites, and only a
minor proportion of tacrolimus dose is eliminated as unchanged parent drug [36]. Metabolism
of tacrolimus leads to the inactivation of the molecule, except for the major 13-O-demethyl
and the minor 31-O-demethyl metabolites. The 13-O-demethyl-tacrolimus possesses some
immunosuppressive effect; however, it is about one tenth as active as tacrolimus, whereas the
31-O-demethyl metabolite displays an immunosuppressive activity comparable to tacrolimus
[37, 38]. On the other hand, high blood concentration of 15-O-demethyl-tacrolimus metabolite
has been reported to be associated with nephrotoxicity and myelotoxicity and with higher
incidence of infections [39]. Similarly to ciclosporin, tacrolimus is metabolized by CYP3A
enzymes, anticipating great interindividual and intraindividual differences in pharmacokinet-
ics of tacrolimus: (1) CYP3A activity of enterocytes contributes to the first-pass metabolism of
tacrolimus; (2) substantial interindividual differences in hepatic CYP3A activity result in great
variability in the rate of tacrolimus metabolism, which requires continuous drug monitor-
ing and dose modification primarily in the early postoperative period; (3) concomitant treat-
ment with CYP3A inhibitors is the potential source of metabolic drug interactions; (4) genetic
polymorphisms of CYP3A5 also contribute to the high interindividual variability. Since the
relative contribution of CYP3A5 to tacrolimus biotransformation is significantly higher than
that of CYP3A4 [40], the recipients carrying wild type CYP3A5*1 allele or transplanted with
liver grafts carrying CYP3A5*1 are able to metabolize tacrolimus more rapidly than CYP3A5
nonexpressers [35, 41].
3.2. mTOR (mammalian target of rapamycin) inhibitors
The mTOR inhibitors prevent cell proliferation by blocking cell cycle progression from the
G1-phase to the S-phase. The immunosuppressive activity is mediated via blocking mTOR
protein kinases, resulting in inhibition of growth factor–mediated T-cell proliferation in
response to IL-2 trigger [42]. Sirolimus is a 31-membered macrolide, whereas everolimus is
a sirolimus derivative having a 2-hydroxyethyl chain substitution at position 40. Although
the chemical structures of sirolimus and everolimus are similar to that of tacrolimus, the
mechanism of action of mTOR inhibitors is distinct from calcineurin inhibitors, which allows
the application of combination regimens. Additionally, the main advantages of mTOR inhibi-
tors are their nonnephrotoxic properties; therefore, mTOR inhibitors in combination with
reduced dose calcineurin inhibitors can augment the calcineurin inhibitor–induced nephro-
toxicity [43–45].
The structural similarities can explain some common metabolic pathways of mTOR inhibitors
and tacrolimus, such as O-dealkylation and hydroxylation at several positions [42]. Sirolimus is
primarily metabolized by CYP3A enzymes and by CYP2C8 at lower extent, producing hydrox-
ylated and O-demethylated metabolites (e.g., 12-hydroxy-, 16-O-demethyl-, 39-O-demethyl-,
27–39-O-didemethyl- and dihydroxy-sirolimus as major metabolites) [46, 47]. The metabolism
of sirolimus leads to inactivation, despite the fact that some metabolites display some phar-
macological activity less than one tenth of the parent drug. Everolimus is also metabolized by
CYP3A and CYP2C8 enzymes; however, the elimination rate of everolimus is more rapid than
sirolimus (with 30 h vs. 62 h elimination half-lives, respectively). Everolimus is O-demethylated
and hydroxylated at several positions (forming both mono- and dihydroxy-metabolites); further-
more, a ring-opened metabolite is also formed from everolimus [46]. Everolimus-induced adverse
effects are associated with the exposure rather to the parent compound than to its metabolites.
3.3. Antimetabolite purine analogues
One of the oldest agents with immunosuppressive activity introduced for kidney transplant
recipients was the purine analogue 6-mercaptopurine, which acts by inhibiting purine nucle-
otide synthesis and, as a consequence, cell proliferation. The prodrug of 6-mercaptopurine,
azathioprine with more favorable side-effect profile was later introduced to prevent rejection.
Azathioprine is converted to 6-mercaptopurine by nonenzymatic cleavage of the thioether in
enterocytes and hepatocytes or in erythrocytes. The major active metabolites, 6-thioguanine
nucleotides, are formed via 6-thioinosine monophosphate in natural purine synthetic pathways.
Inhibition of cell proliferation is mediated by incorporation of the thiopurine nucleotide ana-
logues into DNA (and RNA), causing DNA damage [48]. 6-Mercaptopurine, independently from
either direct administration or production from azathioprine, undergoes metabolic inactivation
by xanthine oxidase and thiopurine S-methyl transferase and is excreted in the urine, leaving less
parent compound available to form thiopurine nucleotides [49]. Due to genetic polymorphism,
the thiopurine S-methyl transferase activity is highly variable in patients; namely, those subjects
who carry one or two nonfunctional thiopurine S-methyl transferase alleles are unable to toler-
ate normal doses of azathioprine and can experience serious myelosuppression [50]. Therefore,
genotyping assay is recommended before starting azathioprine therapy to identify high-risk
patients, and dosage reduction or alternative therapy is recommended for these patients.
3.4. Inosine monophosphate dehydrogenase inhibitors
Mycophenolic acid is a selective inhibitor of inosine monophosphate dehydrogenase, which is

responsible for de novo biosynthesis of guanosine monophosphate, one of the building blocks
of DNA. Depletion of the guanosine pool in the cell arrests the lymphotic cell proliferation
and suppresses the subsequent immune response triggered by allogenic transplanted organ
[51]. In several rapidly dividing cells (e.g. enterocytes), an alternative salvage pathway exists
for purine synthesis in addition to de novo synthetic pathway; however, lymphocytes seem to
be dependent on the de novo pathway. Consequently, mycophenolic acid is able to selectively
block proliferation of T- and B-cells. Mycophenolic acid is available as enteric-coated myco-
phenolate sodium and as mycophenolate mofetil ester prodrug that is extensively hydrolyzed
to the active metabolite mycophenolic acid by carboxylesterases.
Mycophenolic acid is primarily metabolized by UDP-glucuronyl transferases (UGT1A7/8/9,

UGT2B7), forming the major 7-O-mycophenolic glucuronide that is pharmacologically inactive
and to the minor acil-glucuronide that has pharmacological activity comparable to the myco-
phenolic acid [52, 53]. The major proportion of the glucuronide conjugates is excreted in urine,
whereas a smaller proportion that is eliminated via bile is metabolized by bacteria in the gut,
and the deconjugated mycophenolic acid can be reabsorbed (enterohepatic circulation) [54].
Furthermore, in patients’ blood and urine, a minor demethylated metabolite (6-O-demethyl-
mycophenolic acid) was also detected that was proved to be produced by CYP3A enzymes.
3.5. Corticosteroids
At the beginning of transplantation history, glucocorticosteroids were the primary immu-

nosuppressive agents in the rejection prophylaxis strategy, and nowadays, they are still the
first-line agents for treatment of graft rejection. The high-dose glucocorticoids given in peri-
transplantation are tapered to low doses in the maintenance phase, aiming the steroid-free
immunosuppression regimens because of serious adverse effects of glucocorticoids developing
in long-term therapy. Acute rejection is generally treated with methylprednisolone, whereas
the maintenance therapy applies either methylprednisolone or prednisone. Corticosteroids
activate the cytosolic glucucorticoid receptor and modulate several cellular functions, includ-
ing transcription of genes involved in proliferative and inflammatory processes. The activated
receptor inhibits the transcription of NF-kB and activator protein 1 dependent genes, includ-
ing proinflammatory cytokines (Figure 1). This process leads to the depletion of T-cells and
macrophage dysfunction [55].
Regioselective and stereospecific hydroxylation of corticosteroids at several positions (at car-

bon 2, 6, 7, 15, 16, and 21) are catalyzed by CYP3A enzymes. Additionally, dual effect of cor-
ticosteroids on CYP3A enzymes has been demonstrated: (1) corticosteroids can competitively
inhibit the function of CYP3A [56], and (2) they can induce CYP3A transcription. Activated
glucocorticoid receptor upregulates the expression of nuclear receptors (PXR and CAR) that
are involved in transcriptional regulation of CYP3A genes. Moreover, the proximal promoter
region of CYP3A4 gene contains glucocorticoid responsive element, which directly binds acti-
vated glucocorticoid receptor [18, 57]. As a consequence of increased expression and activity
of CYP3A enzymes, metabolic drug interactions can be expected upon concomitant treatment
with drugs that require CYP3A activity for their metabolism.
3.6. Novel investigational immunosuppressant agents
Although calcineurin inhibitor–based immunosuppression efficiently prevents rejection,

adverse reactions of ciclosporin and tacrolimus, primarily nephrotoxicity, prompt the discov-
ery of novel agents with immunosuppressive activity [58]. Two investigational agents with low
molecular weight should be mentioned: voclosporin and sotrastaurin. Voclosporin, a next-gen-
eration calcineurin inhibitor, is an analogue of ciclosporin with a single carbon extension added
to the amino acid-1 of ciclosporin. Voclosporin displays higher binding affinity to cyclophillin
A than ciclosporin leading to more potent inhibition of calcineurin [59]. Furthermore, it has a
favorable safety property that it appears to be less toxic than currently available calcineurin
inhibitors. Similarly to ciclosporin, voclospiron is a substrate for CYP3A enzymes, anticipat-

ing pharmacokinetic/metabolic drug interactions with those agents that interact with ciclo-
sporin as well [60]. However, voclosporin is no longer pursed in transplantation. Sotrastaurin
is protein kinase C inhibitor that effectively inhibits IL-2 production with the mechanism dif-
ferent from calcineurin or mTOR inhibition. Although sotrastaurin displayed some potential
in preventing allograft rejection in animal studies, high efficacy and safety failure rate were
observed in clinical trials involving kidney and liver transplant patients [61, 62]. Therefore,
further development of sotrastaurin in transplantation has been halted.
4. Significant metabolic drug interactions with immunosuppressants
4.1. Combined immunosuppressive therapy
Transplant recipients’ immunosuppressive therapy is often a multidrug therapy, primarily in

the early postoperative period, which constitutes a challenge for clinicians to consider the com-
plexity of drug interactions. Due to the fact that the metabolism of immunosuppressants with
low molecular weight is catalyzed by the same enzymes (CYP3A4 and CYP3A5), the blood con-
centrations, elimination half-lives, and consequently, the efficacy or toxicity of certain immu-
nosuppressant agents are expected to be modified during concomitant treatment. Therefore,
during multidrug therapy or during withdrawal of any of the immunosuppressive drugs, spe-
cial attention is required for optimal dosing for therapeutic concentrations. Each modification
in immunosuppressive regimens can lead to changes in blood concentration of a drug (Table 2).
Calcineurin inhibitors are often applied in combination with mTOR inhibitors. Since both
mTOR inhibitors and calcineurin inhibitors are substrates of CYP3A enzymes and can inhibit
CYP3A activities, reduction of calcineurin inhibitor doses is recommended. Standard doses of
ciclosporin were observed to decrease the clearance of sirolimus or everolimus more substan-
tially than the doses of tacrolimus [45]. The major drawback of calcineurin inhibitor therapy is
the risk of nephrotoxicity which appears to be dose dependent. The combination of low calci-
neurin inhibitor doses with mTOR inhibitors was found to be beneficial regarding retaining low
rejection rates and lowering the risk of nephrotoxicity [44, 63]. To avoided renal dysfunction,
the complete substitution of calcineurin inhibitors for mTOR inhibitors was attempted; how-
ever, the substitution showed an increase in graft failure in patients treated with merely mTOR
inhibitors [64].
Corticosteroids have been demonstrated to induce the expression of the efflux pump trans-
porter ABCB1 (P-glycoprotein) playing a main role in intestinal drug absorption and of CYP3A
enzymes responsible for the metabolism of the majority of drugs [18, 65]. Therefore, the con-
comitant treatment of calcineurin inhibitors or mTOR inhibitors with corticosteroids can be
expected to decrease the blood concentrations of tacrolimus/ciclosporin or of sirolimus/evero-
limus. Although the evidence for clinically significant interactions between corticosteroids and
ciclosporin or mTOR inhibitors is limited, clear clinical effect of corticosteroids on tacrolimus
exposure has been demonstrated [66, 67]. This also implies that dose reduction or cessation
of corticosteroids leads to an increase in blood concentrations of tacrolimus, requiring dose
Immunosuppressant Drug interactions Consequences

Ciclosporin sirolimus, everolimus Increased blood levels of ciclosporin and mTOR
inhibitors; increased risk of nephrotoxicity
Tacrolimus
prednisolone Decreased blood levels due to enhanced

metabolism of ciclosporin/tacrolimus, increased
risk of rejection
Antifungals:
ketoconazole Increased blood levels of ciclosporin/tacrolimus;

replacement of ketoconazole to other azole
derivatives
fluconazole, voriconazole, Inhibition of CYP3A4; dose reduction of

itraconazole ciclosporin, tacrolimus is necessary
Antibiotics:
clarithromycin, erythromycin, Irreversible inhibition of CYP3A4; increased blood

azithromycin levels of ciclosporin/tacrolimus
rifampicin CYP3A4 induction; enhanced metabolism of

ciclosporin, tacrolimus; increased risk of rejection
Antiviral agents:
ritonavir Irreversible inhibition of CYP3A4; increased blood

levels of ciclosporin/tacrolimus
Lipid-lowering agents:
fluvastatin, simvastatin, Increased statin exposure by ciclosporin; incrased

atorvastatin risk of myopathy and rhabdomyolysis
Antihypertensive agents:
diltiazem, verapamil, amlodipine Irreversible inhibition of CYP3A4, formation of

metabolic intermediate complex;
Increased blood levels of ciclosporin / tacrolimus
nifedipine Reversible, competitive inhibition CYP3A4
carvedilol Inhibition of ABCB1 transporter; increase

absorption of oral ciclosporin
Antidiabetic agents:
troglitazone, rosiglitazone CYP3A4 induction; enhanced metabolism of

ciclosporin/tacrolimus; increased risk of rejection
Psychopharmacons:
carbamazepine, valproic acid CYP3A4 induction; enhanced metabolism of

fluvoxamine Inhibition of CYP3A4; contraindicated
Herbs:
St John’s wort CYP3A4 induction; enhanced metabolism of

grapefruit, pomelo Irreversible inhibition of CYP3A4; increased blood

levels of ciclosporin/tacrolimus

Sirolimus ciclosporin Increased blood levels of ciclosporin and mTOR
inhibitors; increased risk of nephrotoxicity
Everolimus
prednisolone Decreased blood levels due to enhanced

metabolism of sirolimus/everolimus, increased risk
of rejection
Antifungals:
ketoconazole Increased blood levels of mTOR inhibitors;

replacement of ketoconazole to other azole
derivatives
fluconazole, voriconazole, Inhibition of CYP3A4; dose reduction of sirolimus,

itraconazole everolimus is necessary; voriconazole – sirolimus
combination is contraindicated
Antibiotics:
clarithromycin, erythromycin, Irreversible inhibition of CYP3A4; increased blood

azithromycin levels of sirolimus/everolimus

sirolimus/everolimus; increased risk of rejection
Antiviral agents:

levels of sirolimus/everolimus
Antihypertensive agents:
diltiazem, verapamil, amlodipine Irreversible inhibition of CYP3A4, formation of

metabolic intermediate complex;
Increased blood levels of sirolimus/everolimus;
verapamil-sirolimus combination is associated with
increased blood levels of verapamil
Antidiabetic agents:
troglitazone, rosiglitazone CYP3A4 induction; enhanced metabolism of

Psychopharmacons:
carbamazepine, valproic acid CYP3A4 induction; enhanced metabolism of

Herbs:
St John’s wort CYP3A4 induction; enhanced metabolism of

grapefruit, pomelo Irreversible inhibition of CYP3A4; increased blood

levels of sirolimus/everolimus
6‑mercaptopurine allopurinol Inhibition of xantine oxidase; myelotoxicity

Azathioprine
Mycophenolate Ciclosporin Inhibition of enterohepatic circulation, decrease in

blood levels of mycophenolic acid

Antiviral agents:
ganciclovir, valganciclovir Mycophenolate-glucuronide inhibits renal tubular

secretion of ganciclovir; increased blood levels
of ganciclovir and increased risk of toxicity
(nephrotoxicity, neutropenia, leukopenia)
Prednisolone Antifungals:
Methylprednisolone
ketoconazole, fluconazole, Increased blood levels of corticosteroids

voriconazole, itraconazole
Inhibition of CYP3A4
Antibiotics:

corticosteroids
Antiviral agents:

levels of corticosteroids
Table 2. Clinically relevant pharmacokinetic drug interactions with immunosuppressants.
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
withdrawal.
Clinically significant interaction between mycophenolic acid, the active metabolite of myco-
phenolate 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, contrib-
uting 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-
mycophenolate to tacrolimus-mycophenolate therapy and vice versa.
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 posttrans-
plant medication. The antifungal azole-derivatives are potent (some of them are very strong)
CYP3A inhibitors, predicting potential metabolic drug interactions with calcineurin inhibi-
tors, 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 con-
comitant treatment with immunosuppressants. However, the widespread use of amphoteri-
cin 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 expo-
sures, 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 ciclo-
sporin/tacrolimus or sirolimus/everolimus increased as a consequences of concomitant treat-
ment 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 immunosup-
pressant 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 cal-
cineurin inhibitors, mTOR inhibitors, and corticosteroids [91–93]. However, blood concentra-
tion–guided dose-adjustment of immunosuppressants should be applied carefully because
increased metabolism can evoke elevation of toxic metabolite formation (e.g., ciclosporin).
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 neph-
rotoxicity 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 thera-
pies 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].
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 expo-
sure [103–106]. In contrast, ciclosporin induces significant elevation of statin blood concentra-
tions 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 rhabdomy-
olysis. 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) fre-

quently 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 immunosuppres-
sants, 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 interac-
tions 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 concomi-
tantly applied. In contrast, no evidence for pharmacokinetic drug interactions has been pro-
vided 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 inhi-
bition of ABCB1-mediated transcellular transport in the intestine by carvedilol is responsible
for the increased absorption of ciclosporin. Under careful monitoring of ciclosporin blood con-
centration, 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 medi-
ated by ABCB1, similar pharmacokinetic drug interactions between these immunosuppres-
sants and carvedilol are presumably developed as with ciclosporin.
4.2.4. Antihyperglycemic therapy
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 trogli-
tazone 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 transcrip-
tion 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 moni-
toring of immunosuppressant blood concentrations is recommended during withdrawal of
troglitazone or rosiglitazone and during switching to other antihyperglycemic agent.
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 psy-
chopharmacons 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 acti-
vation 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 with-
drawal is essential. The comedication with the antidepressant fluvoxamine is contraindicated
because of its strong inhibitory properties for CYP3A4 substrates and potential drug interac-
tions with ciclosporin/tacrolimus or with sirolimus/everolimus [80, 138, 139]. For psychother-
apeutic agents that are CYP3A substrates (haloperidol, quetiapine, clonazepam, midazolam,
alprazolam), continuous monitoring of immunosuppressant blood levels is highly recom-
mended to avoid metabolic drug interactions.
4.2.6. Treatment of hyperuricemia
The metabolic drug interactions with ciclosporin/tacrolimus, sirolimus/everolimus, and corti-

costeroids are generally associated with reversible or irreversible inhibition of CYP3A activi-
ties, as well as with transcriptional induction of CYP3A4 and CYP3A5 expression. Clinically
significant drug interaction occurs during simultaneous therapy with azathioprine (or 6-mer-
captopurine) 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, myelotox-
icity 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-trans-
ferase activity. To avoid the serious myelosuppression during treatment of hyperuricemia and
gout, substantial reduction of azathioprine dose (by at least 50%) is required when allopuri-
nol is given concomitantly, or alternative agents other than allopurinol should be considered
[142–144].
4.3. Metabolic drug interactions between immunosuppressants and herb

components
Pharmacokinetic herb-drug interactions can also significantly influence the outcome of immu-
nosuppressive therapy and long-term graft survival [145]. St John’s wort (Hypericum perfora-
tum) 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 prob-
lems. 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 concentra-
tions 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 hyper-
forin 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 ciclospo-
rin blood concentrations, increasing the risk of rejection; therefore, substantial dose adjustment
is required [151, 152, 155–159]. Since clinicians are often unaware of concomitant consump-
tion 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 dem-
onstrated to increase the bioavailability of immunosuppressants [147, 160, 161]. Some com-
ponents 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/tacroli-
mus 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-
plant patients during immunosuppressive therapy.
5. Concluding remarks
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
therapy. Subtherapeutic blood concentrations of immunosuppressive drugs can evoke acute

or chronic graft injury mediated by immunological mechanisms, whereas overdosing leads to
over-suppression of the immune system that consequently develops serious infections, as well
as adverse and even life-threatening side effects. Because of the narrow therapeutic indexes,
dosing of most of the immunosuppressive agents is applied under careful monitoring of their
blood concentrations. The knowledge of the potential factors that can modify immunosup-
pressive therapy, as well as pharmacokinetic and metabolic drug interactions, can decrease
the fluctuation of immunosuppressant blood concentrations, can facilitate to avoid the seri-
ous adverse events, can improve the therapeutic outcome for transplant patients, and can
reduce the medical costs.
The appropriate and tailored immunosuppressive medication is a great challenge and requires
careful and continuous attention, because unrecognized simple interactions can induce seri-
ous complications. As such during administratrion of clarithromycin or antifungal agents
without dose reduction of calcineurin inhibitors or mTOR inhibitors, blood concentrations
of immunosuppressants can substantially exceed the therapeutic range within some days.
Without dose modification, a reverse outcome is expected during comedication with anti-
convulsants (valproic acid and carbamazepine) or with rifampicin resulting in subtherapeu-
tic blood concentrations of immunosuppressants and increasing the risk of organ rejection.
The lack of mycophenolate dose reduction during cessation of ciclosporin or replacement of
ciclosporin to another immunosuppressant can also evolve development of serious adverse
reactions. It is anticipated that the special attention and the knowledge of potential drug inter-
actions can prevent the majority of misdosing-induced adverse events.
Acknowledgements
This work was supported by MedInProt Synergy VIII program of the Hungarian Academy of
Sciences and by the Society of Hungarian Toxicologists.
Conflict of interest
The author declares that there is no conflict of interest.
Author details
Katalin Monostory
Address all correspondence to: monostory.katalin@ttk.mta.hu

Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of
Sciences, Budapest, Hungary
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Metabolic Drug Interactions With Immunosuppressants

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DOI: 10.5772/intechopen.

Metabolic Drug Interactions with

Keywords: drug metabolism, genetic polymorphism, phenoconversion, calcineurin

2. Genetic and nongenetic variations of drug-metabolizing

The prevalence of loss-of-function or gain-of-function alleles is generally 1–10%; however, the

Immunosuppressants are generally classified according to their molecular mode of action;

Immunosuppressant Pharmacology Adverse effects Enzymes

Ciclosporin Selective inhibition of Nephrotoxicity, hepatotoxicity, CYP3A4/5

Tacrolimus Selective inhibition of Nephrotoxicity, hypertension, CYP3A4/5

Sirolimus Inhibition of B- and T-cell Thrombocytopenia, anaemia, CYP3A4/5

Everolimus Inhibition of B- and T-cell Thrombocytopenia, anaemia, CYP3A4/5

Azatioprin Inhibition of purine Bone marrow suppression, Thiopurine

Mycofenolate mofetil Selective inhibition of Vomiting, diarrhea, abdominal pain UDP-glucuronyl

Prednisone Inhibition of T-cell Adrenal cortex suppression CYP3A4/5

Table 1. Immunosuppressants with low molecular weight.

3.1. Calcineurin inhibitors

1c9-dihydroxy-ciclosporin, 1-carboxy-ciclosporin) are toxic contributing to the nephrotoxic

3.2. mTOR (mammalian target of rapamycin) inhibitors

3.3. Antimetabolite purine analogues

3.4. Inosine monophosphate dehydrogenase inhibitors

Mycophenolic acid is a selective inhibitor of inosine monophosphate dehydrogenase, which is

Mycophenolic acid is primarily metabolized by UDP-glucuronyl transferases (UGT1A7/8/9,

At the beginning of transplantation history, glucocorticosteroids were the primary immu-

Regioselective and stereospecific hydroxylation of corticosteroids at several positions (at car-

3.6. Novel investigational immunosuppressant agents

Although calcineurin inhibitor–based immunosuppression efficiently prevents rejection,

inhibitors. Similarly to ciclosporin, voclospiron is a substrate for CYP3A enzymes, anticipat-

4. Significant metabolic drug interactions with immunosuppressants

4.1. Combined immunosuppressive therapy

Transplant recipients’ immunosuppressive therapy is often a multidrug therapy, primarily in

Immunosuppressant Drug interactions Consequences

prednisolone Decreased blood levels due to enhanced

ketoconazole Increased blood levels of ciclosporin/tacrolimus;

fluconazole, voriconazole, Inhibition of CYP3A4; dose reduction of

clarithromycin, erythromycin, Irreversible inhibition of CYP3A4; increased blood

rifampicin CYP3A4 induction; enhanced metabolism of

ritonavir Irreversible inhibition of CYP3A4; increased blood

fluvastatin, simvastatin, Increased statin exposure by ciclosporin; incrased

diltiazem, verapamil, amlodipine Irreversible inhibition of CYP3A4, formation of

nifedipine Reversible, competitive inhibition CYP3A4

carvedilol Inhibition of ABCB1 transporter; increase

troglitazone, rosiglitazone CYP3A4 induction; enhanced metabolism of

carbamazepine, valproic acid CYP3A4 induction; enhanced metabolism of

fluvoxamine Inhibition of CYP3A4; contraindicated

St John’s wort CYP3A4 induction; enhanced metabolism of

grapefruit, pomelo Irreversible inhibition of CYP3A4; increased blood

Immunosuppressant Drug interactions Consequences

prednisolone Decreased blood levels due to enhanced

ketoconazole Increased blood levels of mTOR inhibitors;

fluconazole, voriconazole, Inhibition of CYP3A4; dose reduction of sirolimus,

clarithromycin, erythromycin, Irreversible inhibition of CYP3A4; increased blood

rifampicin CYP3A4 induction; enhanced metabolism of

ritonavir Irreversible inhibition of CYP3A4; increased blood

diltiazem, verapamil, amlodipine Irreversible inhibition of CYP3A4, formation of

troglitazone, rosiglitazone CYP3A4 induction; enhanced metabolism of

carbamazepine, valproic acid CYP3A4 induction; enhanced metabolism of

St John’s wort CYP3A4 induction; enhanced metabolism of

grapefruit, pomelo Irreversible inhibition of CYP3A4; increased blood

6‑mercaptopurine allopurinol Inhibition of xantine oxidase; myelotoxicity

Mycophenolate Ciclosporin Inhibition of enterohepatic circulation, decrease in

[28] Ryman JT, Meibohm B. Pharmacokinetics of monoclonal antibodies. CPT: Pharmaco