**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,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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].

Beside the genetic polymorphisms, one of the major sources of interindividual or intraindividual 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 androstane 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 (sterile 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 consequence, 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., bergamottin) 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

Metabolic Drug Interactions with Immunosuppressants http://dx.doi.org/10.5772/intechopen.74524 411

drugs with narrow therapeutic index, such as tacrolimus and ciclosporin.

medication at both early and late postoperative periods.

**3. Metabolism of immunosuppressants**

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

In recent decades, transplantation (liver, kidney, heart, and lung) has become a routine procedure for patients with end stage disease. Advances in surgical techniques and postoperative 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

Immunosuppressants are generally classified according to their molecular mode of action; however, in terms of metabolic drug interactions, two main categories must be distinguished

immunosuppressive therapy adjusted to patient's drug-metabolizing capacity.
