**1. Introduction**

The interindividual variability in the metabolism of xenobiotics and drug response is extensive and many factors are involved with this variation including genetic composition, gender, age, co-administration of medication, individual physiology, pathophysiology and presence of other environmental factors (alcohol consumption, smoking, eating habits).

To produce their therapeutic effects, the drug must be present in appropriate concentrations at its site of action. Although the therapeutic concentrations are dependent on the given dose, they will also depend on the magnitude and rate of absorption, distribution, biotransforma‐ tion, and excretion. Pharmacokinetics studies the course and distribution of drug and its metabolites in different tissues, covering the mechanisms of absorption, transport, metabolism and excretion. In addition, pharmacodynamics concentrates on the biochemical and physio‐ logical effects of drugs and their mechanism of action. Proteins involved in drug effects are defined as target molecules and include not only (direct) receptors, but also proteins associated with mechanism of action such as e.g. signal transducer proteins [1].

After its administration, a drug is absorbed and then distributed throughout the body, requiring the coordinated functioning of various proteins, including metabolic enzymes, trafficking proteins, receptor proteins, and others. Medication can enter the body as ei‐ ther active drugs or as inactive prodrugs. Most drugs are metabolized in the liver to make them more soluble for subsequent elimination through the kidneys or intestines. Prodrugs require metabolic conversion, also called biotransformation, to liberate the ac‐ tive compound. Complete biotransformation of any one drug typically requires several different enzymes. [2]. Genetic variability has been described to have effect on drug ab‐ sorption and metabolism and its interactions with the receptors. This forms the basis for

slow and rapid drug absorption, poor, efficient or ultrarapid drug metabolism and poor or efficient receptor interactions [3]. The consequences of such variations can lead to ad‐ verse drug reaction and/or terapeutic failure.

INH-induced adverse reactions include fever, nausea, vomiting, hepatotoxicity, skin reactions, gastrointestinal and neurological disorders. Only in the early 1970s, the occurrence of severe liver injury as a side effect of this drug was recognized, resulting in the death of some patients [8]. Among the first-line anti-TB drugs, INH is the main associated with drug-induced hepatotocixity with a frequency ranging from 1 to 30% in different populations [9]. Other drugs causing liver injury are mainly reported in combination with INH [10, 11]. Drug-induced hepatotoxicity is defined as a serum alanine aminotransferase (ALT) level three times greater than the upper limit of normal (ULN) with clinical symptoms or five times the ULN without symptoms. In both cases treatment should be interrupted and, generally, a modified or alternative regimen is introduced [9]. Because these adverse reactions do not only affect morbidity and mortality rate but also lead to treatment interruptions, failure and relapse, adverse reactions contribute to the spread of the disease and the emergence of multidrug

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Adverse Drug Reactions (ADRs) are common causes of hospitalization and lead to large costs to society. There are two main financial burdens due to illnesses caused by ADRs: that of treating and that of avoiding them [12]. The occurrence of serious and fatal ADRs has been extensively studied in hospitalized patients and a meta-analysis of prospective studies in approximately forty hospitals in the United States of America (USA) suggests that 6-7% of hospitalized patients suffer from serious ADRs and 0.32% of patients develop fatal ADRs [13]. This results in approximately 100,000 deaths annually in the U.S. and an annual cost of over a hundred billion dollars to the society due to prolonged hospitalization and reduced produc‐ tivity [3, 13]. Furthermore, it has been estimated that ADRs are responsible for up to 7% of all admissions in hospitals in the United Kindown (UK) and 13% in medical clinics in Sweden [3], which shows the magnitude of this problem in the context of chemotherapy and drug development. Additionally, in France, a 10-year study in the Liver Unit of Hôpital Beaujon in Paris showed that among all patients hospitalized with acute hepatitis, 10% were due to adverse reaction to drugs and the prevalence of drug hepatotoxicity in patients older than fifty years exceeded 40%. In Japan and other Eastern countries, drugs are responsible for about

Liver injury is the most common ADR and the main complication during chemotherapy since liver is the central organ for the biotransformation and excretion of most drugs and xenobiotics [14-17]. There are basically six mechanisms involving primarily the hepatocyte injury. The reactions of mono-oxygenase cytochrome P450 (CYP450) with certain drugs generate toxic metabolites that bind to intracellular proteins, leading to calcium homeostasis pump dysfunc‐ tion with consequent disruption of actin fibers and cell lysis. Some drugs affect transport proteins in the cell membrane interrupting the flow of bile and then causing cholestasis. Several reactions involving CYP P450 can promote binding of the drug to the enzyme, with consequent exposure of this complex on the cell surface for recognition by T cells and antibody production as part of the autoimmune response. Finally, certain drugs may promote hepatic injury mediated by programmed cell death (apoptosis) or being capable of inhibiting respiration and/

resistence (MDR).

10-20% of cases of fulminant hepatitis [14].

or mitochondrial beta-oxidation [17].

In this context, pharmacogenetics is the study of genetic variations associated with individual variability in drug response, including differences in efficacy, drug-drug interactions, and the relative risk of an adverse response to drugs. It includes the study of genetic polymorphisms that could affect the expression or activity of drug transporters, drug metabolizing enzymes and drug receptors [2-4].

It's estimated that 99.9% of the human genome sequence between individuals is identical and genetic differences in polulations are called mutations if they are present in less than 1% and polymorphisms when present in at least 1% of a population. A single-nucleotide polymor‐ phism (SNP) involves a replacement of one nucleotide base with any one of the other three and occuring at approximately one out of every 1,000 bases in the human genome [5].

A mutation or polymorphism in genes that encode metabolic enzymes, carriers or receptors can affect the drug pharmacokinetics and pharmacodinamics leading to undesired therapeutic effects. The identification of these genetic markers which predicted if a person responds well or not to a specific drug could help to select the right medication in right dosage, maximizing the eficacy and preventing or reducing the adverse drug reactions.
