**4.1. Genes and drugs in transplantation**

**DRUG BIOMARKER DRUG BIOMARKER** Abacavir HLA-B\*5701 Irinotecan UGT1A1 Aripiprazole CYP2D6 Isosorbide and Hydra-lazine62 NAT1, NAT2 Arsenic Trioxide PML/RARα Ivacaftor CFTR Atomoxetine CYP2D6 Lapatinib Her2/neu Atorvastatin LDL receptor Lenalidomide Chromosome 5q Azathioprine TPMT Letrozole ER &/ PgR receptor

292 Current Issues and Future Direction in Kidney Transplantation

Boceprevir IL28B Maraviroc CCR5 Brentuximab Vedotin CD30 Mercaptopurine TPMT Busulfan Ph Chromosome Metoprolol CYP2D6 Capecitabine DPD Modafinil CYP2D6

Carisoprodol CYP2C19 Nortriptyline CYP2D6 Carvedilol CYP2D6 Omeprazole CYP2C19 Celecoxib CYP2C9 Panitumumab EGFR, KRAS Cetuximab EGFR, KRAS Pantoprazole CYP2C19 Cevimeline CYP2D6 Paroxetine CYP2D6

Chloroquine G6PD Perphenazine CYP2D6 Cisplatin TPMT Pertuzumab Her2/neu Citalopram CYP2C19, CYP2D6 Phenytoin HLA-B\*1502 Clobazam CYP2C19 Pimozide CYP2D6 Clomiphene Rh genotype Prasugrel CYP2C19 Clomipramine CYP2D6 Pravastatin ApoE2 Clopidogrel CYP2C19 Propafenone CYP2D6 Clozapine CYP2D6 Propranolol CYP2D6 Codeine CYP2D6 Protriptyline CYP2D6 Crizotinib ALK Quinidine CYP2D6 Dapsone G6PD Rabeprazole CYP2C19 Dasatinib Ph Chromosome Rasburicase G6PD

Denileukin Diftitox CD25 Rifampin, Isoniazid, and

Dexlansoprazole CYP2C19, CYP1A2 Sodium Phenylacetate and

Desipramine CYP2D6 Risperidone CYP2D6

Diazepam CYP2C19 Tamoxifen ER receptor Doxepin CYP2D6 Telaprevir IL28B

Erlotinib EGFR Tetrabenazine CYP2D6 Esomeprazole CYP2C19 Thioguanine TPMT Everolimus Her2/neu Thioridazine CYP2D6

Chlordiazepoxide and Amitriptyline

Dextromethorphan and

Drospirenone and Ethinyl

Quinidine

Estradiol

Carbamazepine HLA-B\*1502 Nilotinib Ph Chromosome, UGT1A1

CYP2D6 Peginterferon alfa-2b IL28B

Pyrazinamide

Sodium Benzoate

CYP2C19 Terbinafine CYP2D6

CYP2D6 Sodium Phenylbutyrate UCD (NAGS; CPS; ASS; OTC; ASL;

NAT1; NAT2

ARG)

ARG)

UCD (NAGS; CPS; ASS; OTC; ASL;

In the pharmacogenetics of transplantation, as in other therapeutic areas, three groups of genes specifically involved in the response to immunosuppressive therapy have been identified: the genes encoding drug transporter proteins, inward or outward of the cells; the genes encoding metabolic enzymes involved in drug biotransformation and, finally; those encoding receptors or drug targets. Although the great majority of immunosuppressive drugs are transported and metabolized by a limited set of enzymes which mostly are known genes, the interpretation of the results observed in transplanted patients is complicated in many times. One reason for this is that these patients are highly subjected to polytherapy, and so interactions, both pharma‐ cokinetic and pharmacodynamic, may have great significance and may condition the response to treatment. Another important aspect to consider when interpreting the observed response is the fact that each patient actually contains two different genetic entities: the donor and the recipient. This phenomenon is particularly relevant when the transplanted organs are the liver or the kidney. In these types of transplantation, it must be considered that the drugs admin‐ istered to the recipient will be metabolized or excreted by the transplanted organ from the donor. In fact, more and more studies in transplantation pharmacogenetics consider both the donor and recipient genotypes to evaluate the response to treatment [9-12].

Moreover, one of the main problems of pharmacogenetic studies is the difficulty to recruit the number of patients needed to achieve sufficient statistical power and demonstrate conclusively the existence of significant clinically relevant differences according the different genotypes, that is, according to the different alleles or variants of a polymorphic site. This is due to the uneven distribution of allele frequencies in the population, which makes it difficult to collect a large enough number of individuals to study minor genotypes. Furthermore, the distribution of allelic frequencies in some genes varies according to ethnicity so, for instance, the expected frequencies of each allele of a polymorphic site in the Caucasian population are not the same as in the Asian. The expected effects of each allelic variant are presumably the same, but the ease for recruiting different genotype patients is not.

**4.2. Pharmacogenetic examples in renal transplantation**

consolidated conclusion about the first three drugs.

tacrolimus or cyclosporine.

sants are shown in table 2.

ABCB1 *transport*

CYP3A5 *metabolism*

CYP3A4

UGT1A9 *metabolism*

ABCC2 *transport*

IMPDH1 *target*

IMPDH2 *target*

SLCO1B1 *transport*

Tacrolimus Cyclosporine

Mycophenolic Acid

**DRUG GENE SNP Effect**

rs1045642 C>T; 3435 C>T

rs776746 A>G; \*1 (A), \*3 (G)


C-24T C3972T

3757 T>C

*metabolism* Implications not clearly defined

Pharmacogenetic information of immunosuppressants in renal transplantation is mainly related to Tacrolimus, Cyclosporine and Mycophenolic Acid. Sirolimus, Everolimus and Corticoids are also being studied but to a much lesser extent, so we will focus here on the most

Practical Pharmacogenetics and Single Nucleotide Polymorphisms (SNPs) in Renal Transplantation

http://dx.doi.org/10.5772/54733

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The first two, being both Calcineurin Inhibitors (CNI), share their mechanism of action and so, share transporters, metabolism enzymes and targets and therefore, they also share pharma‐ cogenetic results in most of the cases. The fact that they are both subject of a controlled therapeutic drug monitoring, with "in some way" standardized blood measuring methods, has allowed the publication of many works dealing with correlations between drug levels and polymorphisms [14-23]. To a lesser extent, there are also many works correlating drug adverse effects with SNPs [24-28]. The therapeutic drug monitoring of mycophenolic acid is not as followed as for CNIs, as there is not such a clear consensus about the effects of different blood levels in the possible drug related toxicity. However, many efforts have also been done in the pharmacogenetic studies of this drug [29-36], as it is widely employed in combination with

The most consensuated genes regarding polymorphic effects on these three immunosuppres‐

C: higher transporter activity, less drug absorption T: lower transporter activity, more drug absorption

metabolizing the drug, so they need lower doses

rejection in patients with fixed dose MFA+Tac

Implications not clearly defined

rs2278293 Higher risk of leucopenia, lower risk of BPAR

**Table 2.** Most studied SNPs related to Tacrolimus, Cyclosporine and Mycophenolic Acid in Renal Transplantation.

As shown in the table, even in these SNPs that are the most extensively studied, the clinical implications are not always well established. Many more other SNPs are currently under

rejection)

\*5 Implications not clearly defined

Allele \*1 carriers have functional enzyme and require higher drug doses to reach target levels. Allele \*3 carriers have nonfunctional allele, the enzyme is not


C: higher IMPDH activity, higher incidence of BPAR (biopsy-confirmed acute

Figure 1 shows, in summary, an integrator scheme with the best known genes encoding transporter proteins and enzymes involved in the metabolism of several drugs commonly used in transplantation.

**Figure 1.** Integrative scheme of pharmacogenetic genes related to transport and metabolism of immunosuppressive drugs for transplantation. (Adapted from ref. 13, ©Astellas Pharma S.A. y Master Line & Prodigio S.L.). The drawing shows a broad view of the location and influence of metabolic enzymes and transporters on the main immunosup‐ pressive drugs used in transplantation. The integrated view of many of the genetic factors that influence the achieve‐ ment of therapeutic and stationary blood levels, should allow a better interpretation of pharmacogenetic data and also, help improve the safe and effective use of medication.
