**3. Metabolism of immunosuppressants**

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

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 evidenced [6–9]; however, the heritable genetic polymorphisms are not the only determinant factors 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

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 populations; 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 clinical 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 association between *CYP3A4* genotype and pharmacokinetic behavior of CYP3A-substrates has been extensively studied, no clear phenotype-genotype relationship has been described for CYP3A4.

**2. Genetic and nongenetic variations of drug-metabolizing** 

of tailored pharmacotherapy [4, 5].

**cytochrome P450 (CYP) enzymes**

410 Organ Donation and Transplantation - Current Status and Future Challenges

estimation of a patient's drug-metabolizing capacity.

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 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


according to their molecular weights (agents with low or high molecular weights). Highmolecular-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-metabolizing CYP enzymes are involved which may entail metabolic drug interactions (**Table 1**).

Metabolic Drug Interactions with Immunosuppressants http://dx.doi.org/10.5772/intechopen.74524 413

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-

Ciclosporin A is an 11-amino acid cyclopeptide that blocks the production of IL-2 by inhibition 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, hydroxylation 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.

**3.1. Calcineurin inhibitors**

trations for optimal safety and therapeutic efficacy.

**Table 1.** Immunosuppressants with low molecular weight.

according to their molecular weights (agents with low or high molecular weights). Highmolecular-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-metabolizing CYP enzymes are involved which may entail metabolic drug interactions (**Table 1**).
