Pharmacogenomics & Pharmacogenetics

Pharmacogenetics is the study of interindividual variations in DNA sequence related to drug response. With pharmacogenetics we can understand how genomic factors associated with genes encoding enzymes responsible for drug metabolism regulate pharmacokinetics and pharmacodynamics (mostly safety issues). Pharmacogenomics is the study of the variability of the expression of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level. The term is broadly applicable to drug design, discovery, and clinical development. With pharmacogenomics we can differentiate the specific disease-modifying effects of drugs (efficacy issues) acting on pathogenic mechanisms directly linked to genes whose mutations determine alterations in protein synthesis or subsequent protein misfolding and aggregation.

Additional Information

a. The term drug should be considered synonymous with investigational (medicinal) product, medicinal product, medicine, and pharmaceutical product (including vaccines and other biological products). b. Pharmacogenetics and Pharmacogenomics are applicable to activities such as drug discovery, drug development, and clinical practice. c. Drug response includes the processes of drug absorption and disposition (e.g., pharmacokinetics (PK)), and drug effects (e.g., pharmacodynamics (PD), drug efficacy, and adverse effects of drugs). d. The definitions of Pharmacogenetics and Pharmacogenomics do not include other disciplines such as proteomics and metabolomics.

Drug Metabolism

Drug metabolism is the biochemical modification or degradation of drugs, usually through specialized enzymatic systems. The xenobiotic-metabolizing enzymes convert drugs into compounds called metabolites that are hydrophilic derivatives that are more easily eliminated through excretion into the aqueous compartments of the tissues. The primary mode of excretion is through the kidneys. Thus, the process of drug metabolism that leads to elimination plays a major role in diminishing the biological activity of a drug. Xenobiotic metabolizing enzymes have been grouped into the phase 1 reactions, in which enzymes carry out oxidation, reduction, or hydrolytic reactions, and the phase 2 reactions, in which enzymes form a conjugate of the substrate (the phase 1 product). The primary site of drug metabolism is the liver and the most important family of liver isoenzymes is cytochrome P-450 (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, mainly) that metabolizes a high percentage of drugs used in clinical practice. These enzymes participates in phase I metabolism producing an oxidation reaction. Drug interactions can occur when one drug induces or inhibits P-450 enzymes that act on another drug, reducing its effect or increasing its concentration to toxic levels. In addition, certain foods, such as grapefruit juice, or medical situations, such as liver diseases, can inactivate or lessen the metabolic activity of P-450s building up to toxic levels. Changing the drug dosage can alleviate the problem in some cases. The metabolic rate can vary significantly from person to person, and drug dosages that work quickly and effectively in one individual may not work well for another. Factors such as genetics, environment, nutrition, and age also influence drug metabolism; infants and elderly patients may have a reduced capacity to metabolize certain drugs, and may require adjustments in dosage.

Phase I

The majority of commonly used drugs, in order to unleash their therapeutic action, once administered via their different routes (oral, cutaneous, subcutaneous, intramuscular, intravenous, intrathecal, nasal, etc.), are absorbed and enter the bloodstream, by means of which they reach their therapeutic targets and/or pass through the liver, where they undergo a chemical transformation process, which permits their subsequent elimination. Drug metabolism requires Phase I and Phase II reactions. Phase I reactions are mediated by enzymes that cause oxidation, reduction and hydrolysis; and Phase II reactions are usually conjugation reactions caused by enzymes that act by acetylation, glucuronidation, sulfatation and methylation.
We know that genes contain variations in their nucleotide sequence developed during evolution. Variations located in a codifying region may lead to substitution of an amino acid in a specific position of a protein and consequently may affect protein function. When variations occur in a regulatory region with a 1% allelic frequency or greater in a population is defined as polymorphism, they may influence transcriptional and translational mechanisms with consequent modulation of gene product (mRNA and proteins) expression levels.
Genetic variations concerning single base pair substitutions, the simplest genetic variants, are defined as single nucleotide polymorphisms (SNPs). Genetic variations may also involve several nucleotides or long DNA traits. In this case they are considered large mutations and defined substitutions, insertions, deletions, amplifications and translocations.
More than one-third of human genes have been found to be polymorphic. A change in the nucleotide sequence of a gene can lead to a change in the amino acid sequence of the protein and altered enzymatic activity, protein stability, and binding affinities. Genetic variation can thus affect drug efficacy and safety when the mutations occur in proteins that are drug targets (e.g., receptors), are involved in drug transport mechanisms (e.g., ion channels), or are drug-metabolizing enzymes.
Gene polymorphisms codify for enzymes characterized by different metabolic activity or receptors with different affinity for the drug. They modify the pharmacological response in individuals or, in case of variations particularly frequent, in some ethnic groups.
In Phase I reactions, which are the most frequent and most significant in the metabolism of many drugs, different pharmaceutical products act as substrates of a particular enzyme; though they may also act by inhibiting or inducing the activity of other enzymes on which the drug does not act as a substrate. The most important group of phase I genes is the P-450 superfamily (CYPs), which embraces over 200 genes present in the majority of species and evolved throughout the phylogenetic scale to protect us against environmental toxins and other types of substance potentially harmful. These genes encode oxido-reductase enzymes that biotransform the chemical substances consumed by our organism, converting them into metabolites, some of these apparently harmless, others therapeutic, and a few highly toxic, being subsequently excreted in the urine, feces or bile.
The principal enzymes with polymorphic variants involved in phase I reactions are the following: CYP3A4/5/7, CYP2E1, CYP2D6, CYP2C19, CYP2C9, CYP2C8, CYP2B6, CYP2A6, CYP1B1, CYP1A1/2, epoxide hydrolase, esterases, NQO1 (NADPH-quinone oxidoreductase), DPD (dihydropyrimidine dehydrogenase), ADH (alcohol dehydrogenase), and ALDH (aldehyde dehydrogenase).

Phase II

Enzymes involved in phase II reactions (i.e., acetylation, glucuronidation, sulfation, methylation) include the following: UGTs (uridine 5’-triphosphate glucuronosyl transferases), TPMT (thiopurine methyltransferase), COMT (catechol-O-methyltransferase), HMT (histamine methyltransferase), STs (sulfotransferases), GST-A (glutathion S-transferase A), GST-P, GST-T, GST-M, NAT2 (N-acetyl transferase), NAT1, and others. Polymorphisms in genes associated with phase II metabolism enzymes, such as GSTM1, GSTT1, NAT2 and TPMT are well understood, and information is also emerging on other GST polymorphisms and on polymorphisms in the UDP-glucuronosyltransferases and sulfotransferases.


Transport proteins play an important role in regulating the absorption, distribution, and excretion of many medications. There are three major groups or superfamilies of transporters: Solute carrier (SLC) transporters, Solute carrier organic anion (SLCO) transporters, and ATP-binding cassette (ABC) tranporters.
The SLC group of membrane transport proteins includes over 300 members organized in 51 families. SLCO transporters include 11 members grouped in 6 families, and the ABC family of membrane transporters with 50 members. Members of the ATP-binding cassette family of membrane transporters are among the most extensively studied transporters involved in drug disposition and effects. An example is the P-glycoprotein encoded by the human ABCB1 gene (also called MDR1 or Multi Drug Resistence protein). A principal function of ABCB1 is the energy-dependent cellular efflux of substrates, including bilirubin, several anticancer drugs, cardiac glycosides, immunosuppressive agents, glucocorticoids, HIV type 1 protease inhibitors, and many other drugs.

Personalized Therapy

This consists of choosing the right drug for each patient and the dosage of that drug which is appropriate for each individual. In this way, depending on the result obtained in the genetic test, the therapy will be addressed differently:

  • Ultra-rapid Metabolizers (UM): These are the individuals who metabolize drugs most rapidly.Caution is recommended when prescribing drugs metabolized by these enzymes.It is advisable to monitor the patient due to possible lack of efficacy of the treatment. It may be necessary to increase the dosage of the drug.* It may be necessary to consider a change of treatment.*
  • Extensive (Normal) Metabolizers (EM):  These are the individuals who metabolize drugs correctly.In principle, it is not necessary to alter the recommended standard dosage of the drug.These individuals do not present a risk of suffering an anomalous response derived from the administration of drugs.The possibility of adverse reactions or ineffective response cannot be dismissed, due to environmental factors.*
  • Intermediate Metabolizers (IM):  These are the individuals who metabolize drugs slightly less effectively than the average.? Caution is recommended when prescribing drugs metabolized by these enzymes. Treatment with multiple drugs should be avoided if these are involved in pharmacological interactions. It is advisable to monitor the patient due to the possible appearance of adverse reactions. A slightly lower drug dosage may be necessary in order to achieve an optimal therapeutic response.*
  • Poor Metabolizers (PM): These are the individuals who do not metabolize drugs effectively. Caution is recommended when prescribing drugs metabolized by these enzymes. It is advisable to monitor the patient due to the possible appearance of adverse reactions. A lower drug dosage may be necessary in order to achieve an optimal therapeutic response.* It may be necessary to consider a change of treatment.*
* To be assessed by the physician while considering the joint appraisal of environmental and genetic factors.