4 Personalized Medicine and Pharmacogenomics
The recognition that a part of interindividual variability in drug response is
inherited, and therefore predictable, created the field of pharmacogenetics/
pharmacogenomics. Genetic variation is considered an important source of vari-
ability in drug response and contributes to 25–50 % of inappropriate drug
responses.^18 It has the potential to negatively impact effectiveness of drug therapy
(drug efficacy) and increases the risk for adverse drug reactions (ADRs).
One type of genetic variation is the single nucleotide polymorphisms (SNPs).
Knowing the types of SNPs/genetic variations can help predict the associated drug
response. This can help physicians to improve effectiveness of the drug, decrease the
chance of negative side effects, and save health care costs. Associations of SNPs to
drug treatment outcome are continuously being discovered, with a recent focus on
genome-wide association (GWA) studies being conducted in many different ethnic
groups.
Interindividual differences in drug disposition are important causes for ADRs
and lack of drug response. There are major interindividual differences in the
capacity to metabolize and detoxify drugs and other xenobiotics. Biotransformation
occurs through phase I and phase II drug-metabolizing enzymes (DMEs), i.e.,
enzymes catalyzing oxidation and conjugation reactions, respectively, with the
important role of drug transporters, named phase III reactions. The majority of
phase I and phase II DMEs and phase III drug transporters are polymorphic and
constitute essential factors for the outcome of drug therapy. In the terms of drug
metabolism, there are four specific phenotypes that can be determined by either
phenotyping or genotyping: a poor metabolizer (PM), intermediate metabolizer
(IM), extensive metabolizer (EM), and ultrarapid metabolizer (UM). A poor
metabolizer lacks active allele and may experience more adverse events at usual
doses due to reduced metabolism and increased drug concentration. If individuals
lacking the active allele receive a prodrug, they may not respond due to a lower-
than-expected concentration of the active metabolite. Individuals with intermediate
metabolic phenotype are homozygous for two reduced activity alleles or are
heterozygous for an inactive allele. They may experience some, or a lesser degree
of, consequences of a poor metabolizer. Extensive metabolizer has two fully active
alleles and shows expected response to a standard dose. Ultraextensive
metabolizers are individuals with more than two copies of active gene. They may
not reach therapeutic concentrations at usual, recommended drug doses due to
increased metabolism. When a prodrug is administered, they may experience
adverse effects due to higher-than-expected concentrations of active metabolite.
Clinically, the most important polymorphisms in phase I are of theCYP2C9,
CYP2C19,CYP2D6andCYP3A4/5genes.^19
Phase II biotransformation processes also show high interindividual variability. Poly-
morphisms of the thiopurine methyltransferase (TPMT), UDP-glucuronosyltransferase
(^18) Spear et al. ( 2001 ).
(^19) Johansson and Ingelman-Sundberg ( 2011 ).
272 D. Vitezic ́et al.