**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 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 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 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.

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 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.
