Pharmacogenomics: Impact on Drug Response and Applications to Infectious Diseases Management

Pande V. V.

The impact of pharmacogenomics on the
prevention, diagnosis, and treatment of infectious diseases is
discussed. The application of pharmacogenomics to infectious diseases
requires consideration of the genomes of both the pathogen and the host.

The pathogen’s genome may be used for antigen
identification, to identify infecting organisms, and to determine
antimicrobial resistance. Diagnostic tool development and vaccine
design can be aided by knowing which portions of a pathogen are
important antigenic determinants. The unique genetic makeup of a
pathogen can facilitate its identification as an augmentation to the
traditional culture. Important genes conferring resistance to
antibiotics can be detected and this information

can be used to choose appropriate antibiotic therapy. The
genome of the host may reveal susceptibility genes and new drug targets
that may be used in the treatment of infectious diseases. Thus far,
polymorphisms in genes of the host immune system have been associated
with susceptibility to infections and response to treatment. Examples
of these findings will be described. Pharmacogenomics has the potential
to revolutionize the prevention, diagnosis, and treatment of infectious
diseases.

Introduction

A drug may work well in one person, but poorly or not at all
in another. One person may tolerate a drug well, whereas another
develops side effects. This fact is as well known, as it is
unfortunate. These individual differences are largely due to our
genome, the genetic blueprint that makes each of us unique. Thanks to
new knowledge and techniques, medicine is now able to take greater
account of these differences thus leading to the development of more
effective, safer and better tolerated drugs. ^{1, 2}

Pharmacogenetics is the investigation of
individual drug metabolism and its relationship with genetic variants
or POLYMORPHISMS. It involves the study of the genetic basis for
individual differences in response to drugs, both therapeutic (for drug
efficacy) and adverse (for drug safety).

Pharmacogenomics concerns the
development of drugs using information about genetic polymorphisms. It
involves in-depth, GENOME-wide evaluations of drug effects.
Pharmaceutical companies may use pharmacogenomics to assist in research
on and development of new drugs. It is the quickly growing field of
science that studies the effects of individual genetic variations on
drug response. The end result of pharmacogenomics research will be to
match an individual's genetic profile to the best drug that will do the
most good with the least harm to the body. ^{3, 4, 5, 6}

Hurdles for Drugs: Genetic Polymorphisms

Genetic differences between individuals strongly influence the function
of the corresponding gene products (usually proteins) and in this way
affect the activity of drugs in the body. Some of these genetic
variants, known as polymorphisms, have been identified. They influence
people’s response to drug therapies at the pharmacokinetic or
pharmacodynamic level.

1. Pharmacokinetics:

Genes coding for enzymes involved in the metabolism of drugs
form the largest group of known pharmacogenetic factors. Fluctuations
in their activity can slow or accelerate the uptake, conversion or
excretion of drugs. As a result, the drugs do not remain in the body
long enough to be effective or remain in the body too long so that the
risk of dangerous side effects increases.

2. Pharmacodynamics:

Some genes have also been found that are directly responsible
for the structure of the target molecule, influence the associated
signaling pathway or interfere with some other metabolic pathway
involved in the manifestations of a disease. The interactions between
such genes and drugs can be highly complex. ^{7, 8, 9}

Application of 
Pharmacogenetics/Pharmacogenomics Technology to Drug Development.

NAS: new active substances
 

Survey of CMR International Institute
for Regulatory Science, 2003.

Applications
^{10, 11, 12,
13}

Pharmacogenetics could be used to determine the
most effective treatment for patients prior to drug
prescription. By screening patients for polymorphisms known to affect
drug metabolism, physicians could determine which available drugs would
have the most therapeutic benefit for the patient, while minimizing any
adverse side effects.

Pharmacogenetics could be used to
‘rescue’ existing drugs that have been
withdrawn from use because of adverse drug reactions in a number of
people. Retrospective genotyping of clinical trial subjects could
identify the genetic make-up of the often small proportion of patients
who suffered adverse reactions. Alternatively, a subgroup of
individuals may be identified who, for genetic reasons, respond well to
the drug and do not suffer side effects. In either case, the drug could
be placed on the market with the proviso that specific genetic tests
are administered prior to drug prescription.

The clinical diagnosis of many
diseases may eventually incorporate pharmacogenetic testing. Test
results could assist clinicians to identify disease subtypes and the
most effective treatment for the disorder.

The process of drug research and development
may be significantly altered by pharmacogenomics. Pharmacogenomic
approaches would focus on the identification of genetically determined
drug targets involved in disease and genetic polymorphisms associated
with treatment response. Such research could assist pharmaceutical
companies to develop more effective drugs with fewer side effects.

Subjects’ eligibility to participate in
clinical trials may be decided by the results of
pharmacogenetic tests. Pharmaceutical in drug response, each containing
numerous polymorphisms that may influence drug metabolism or disease
development. These polymorphisms must be identified before
pharmacogenetic and pharmacogenomic products can be developed. The
complexity of both the human genome, and human diseases, may make it
difficult and time-consuming produce this information.

‘Pharmacogenetic profiles’
that
catalogue both a patient’s genetic predisposition’s
to diseases, and their predicted responses to different drugs could be
used in clinical medicine. This information could be relevant to
clinical decisions, informing physicians of recommended dosages,
possible adverse reactions and potential drug interactions. It may even
become possible to ‘personalise’ medicine, creating
drugs that suit each individual, based on their genotype. (Fig.1)

Figure 1: - Genome Organization

Pharmacogenetic and
Pharmacogenomic Research in Psychiatry: Current Advances and Clinical
Applications

After more than 50 years of investigations, pharmacogenetic
efforts have crystallized in several findings relating genetically
determined pharmacokinetic and pharmacodynamic factors to treatment
response. Metabolic enzymes and neurotransmitter proteins contain
genetic polymorphism that alter their interaction with psychotropic
drugs and contribute to response variability. This knowledge can be
used to predict clinical results and adverse reactions. Current
clinical applications include rapid methods for the characterization of
metabolic status that is used in clinical trials for the identification
of individuals susceptible to side effects. This practice is being
extended to clinical laboratories to avoid toxic reactions to specific
treatments. Pharmacogenetics methods for the pre-treatment prediction
of clinical response to the antipsychotic drugs clozapine, risperidone,
olanzapine and haloperidol are in development and expected to be
available for clinical use in the next decade. However, much is still
expected from the wealth of information produced by pharmacogenomic
research. Pharmacogenomic strategies, including large scale functional
studies in brain areas related to the etiology of mental disorders,
will increase the knowledge on therapeutic mechanisms and identify
novel targets. Pharmacogenomic advances will be translated into more
specific and safer drugs and tailoring of drug prescription according
to the patient’s genetic susceptibilities. Pharmacogenetic
and pharmacogenomic investigations have the potential to transform
psychiatric treatment in the next decades. ^{14, 15}

Pharmacogenetic Variation
in Drug Oxdizing Cyps:
Impact on Drug Therapy, Drug Safety and Drug Interactions

Cytochromes P450 (CYPs) are multifunctional enzymes that are
active in the oxidative metabolism of many drugs and play a dominant
role in the elimination of drugs from the body. Pharmacokinetic
interactions may arise when the biotransformation and elimination of a
drug are impaired by co administered drugs. Thus, drugs may compete for
biotransformation by a common CYP. Adverse drug reactions, including
toxicity, can occur if elimination is dependent on a CYP that exhibits
defective gene variants. Thus, the genetic makeup of the individual is
a major influence on the duration of drug action, as well as drug
efficacy and safety. This review summarizes recent information on the
mechanisms of drug-drug interactions that are due to impaired CYP
function and also outlines the impact of aberrant CYP genes on drug
biotransformation. Evidence is presented that CYP pharmacogenetics
affects the propensity for certain drug-drug interactions. Thus, the
future safe use of drug combinations in patients may require genotyping
and phenotyping of individuals before the commencement of therapy.
Identification of subjects who metabolize drugs in a different fashion
from the general population should minimize the impact of
pharmacogenetic variation on drug pharmacokinetics. ^{16,
17, 18} 

Application
of Genetic Polymorphisms in DNA Repair in the Prediction
of Cancer Susceptibility and Clinical Outcome

The capacity to repair damaged DNA is a basic tool by which
the mammalian cell maintains its genetic integrity and prevents
neoplasm; however, DNA repair function could be modified by genetic
polymorphisms. Recent molecular epidemiological studies have indicated
that these genetic variants occur in the normal population and can be
used to predict individual cancer risk. Since variation in the function
of these genes might impact a cancer cell’s viability or
resistance to treatment, genetic variants in DNA repair might act as a
valuable marker in forecasting the results of cancer treatment. This
possibility has been outlined by some clinical pilot studies of genetic
polymorphisms in the DNA repair genes. With the biological importance
of the DNA repair genes, studies of these genetic variants occurring in
the general population will further our understanding of cancer
etiology and behavior. ^{19, 20}

The Impact of Pharmacogenomics on the Prevention,
Diagnosis, and Treatment of Infectious Diseases

The application of pharmacogenomics to infectious diseases
requires consideration of the genomes of both the pathogen and the
host. The pathogen’s genome may be used for antigen
identification, to identify infecting organisms, and to determine
antimicrobial resistance. Diagnostic tool development and vaccine
design can be aided by knowing which portions of a pathogen are
important antigenic determinants. The unique genetic makeup of a
pathogen can facilitate its identification as an augmentation to the
traditional culture. Important genes conferring resistance to
antibiotics can be detected, and this information can be used to choose
appropriate antibiotic therapy. The genome of the host may reveal
susceptibility genes and new drug targets that may be used in the
treatment of infectious diseases. Thus far, polymorphisms in genes of
the host immune system have been associated with susceptibility to
infections and response to treatment. Pharmacogenomics has the
potential to revolutionize the prevention, diagnosis, and treatment of
infectious diseases. (Fig.2) ^{21, 22, 23, 24}

HLA class I glycoproteins play an important role in viral
infection. Since viruses use their hosts’ cellular machinery
for replication, these cells present viral proteins on their surfaces
by using HLA class I glycoproteins. The presentation of viral peptides
elicits a cell-mediated immune response that destroys the virally
infected cell. Conversely, HLA class II glycoprotein expressed on an
antigen-presenting cell display antigenic peptides derived from the
pathogen. A T cell recognizes the antigenic peptide as foreign and
initiates an immune response to the antigen (Figure 2) ²⁵

Edging Toward
Personalized Medicine

Only 50-75% of patients are estimated to benefit from
successful drugs. Pharmacogenetics research has demonstrated that the
risk of therapeutic failure, drug toxicity and drug interactions is not
the same for everyone and that genetic variation is an important
determinant of these events. With the maturation of the Human Genome
Project, a rational approach to new and better therapies is now viewed
as a realistic prospect that will result in drugs personalized to
small, genetically defined groups of patients or even to individuals.
If treatment is guided by genetic profiles individualized to specific
drugs, we expect to reduce the frequency and severity of adverse drug
reactions. A large set of genetically polymorphic markers predictive of
human drug response is now available. Foremost among these markers is
the family of pharmacokinetic polymorphisms mainly consisting of the
polymorphic human drug metabolizing enzymes. So far, clinical
application of this new knowledge has been limited. ^{26, 27}

Advances
in
Pharmacogenomics Research.

Pharmacogenomics utilizes knowledge of the patient genetic
profile to influence decisions on treatment. It is considered by many
to hold the key to the future of drug research, but some remain
skeptical of its immediate impact. The use of pharmacogenomics will
create medical, ethical, legal, and regulatory pressures that will
cause diagnostic companies to develop rapid high-throughput assays to
optimize patient diagnosis. The impact of these changes will inevitably
require the pharmaceutical and diagnostics industries to collaborate to
meet future demands. ^{28, 29}

Risks and Limitations

Pharmacogenetics and pharmacogenomics are limited by the
identification of relevant polymorphisms. Many genes are likely to be
involved in drug response, each containing numerous polymorphisms that
may influence drug metabolism or disease development. These
polymorphisms must be identified before pharmacogenetic and
pharmacogenomic products can be developed. The complexity of both the
human genome, and human diseases, may make it difficult and
time-consuming produce this information.

Non-genetic factors may also
limit the application of pharmacogenetics and pharmacogenomics.
Genotyping is not sensitive to factors, such as drug-drug interactions
and environmental factors, which can influence disease and treatment
response. Consequently, pharmacogenetic information alone will not
predict the efficacy or safety of a drug. ³⁰

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About
Authors: -

Pande V. V.
^*
Shastri K. V 
, Tekade A. R. 
, Chandorkar J.G.  style="font-weight: bold;"> style="font-weight: bold;"> , Dr. Dubey
Sonal  

Pande V. V. style="font-weight: bold;"> *  style="font-weight: bold;">

Lecturer, Department of Pharmacology, Siddhant College of
Pharmacy,
Pune.     E-mail ID: -
vishalpande1376@gmail.com

style="font-weight: bold;"> style="font-weight: bold;">Shastri K. V

SES’ R. C. Patel College of
Pharmacy, Department
of Pharmacognosy
and Phytochemistry, Karvand Naka, Shirpur- 425
405, Dist. Dhule (M.S.)

 E-mail ID: - keyurshastri@gmail.com

Tekade A. R.

Assistant Professor, Department of
Pharmaceutics, Siddhant
College of Pharmacy,
Pune.     E-mail ID: -
avi_tekade@yahoo.com.

Chandorkar J.G.

Group Principal Scientist, Innovassynth Technologies
Ltd. Khopoli, Dist. Raigad.   
E-mail ID: -
jgchandorkar@innovassynth.com

Dr. Dubey
Sonal

Assistant Professor, Department of Chemistry, 
K.L.E.’s College of
Pharmacy, Rajajinagar, Bangalore.
   

E-mail ID: -drsonaldubey @gmail.com.