The document discusses the history and importance of pharmacogenetics in understanding variability in individual drug response and toxicity. It describes the role of genetic polymorphisms in drug metabolizing enzymes like CYP450 and how this impacts drug clearance and effects. While data on genetic variability is growing, well-designed clinical trials are still needed to validate pharmacogenetic approaches and address the challenges of predicting drug metabolism and response based on genetics. Understanding these factors can help optimize drug therapy and dosing for individual patients.
1. Dr. Obumneke Amadi-Onuoha_Scripts_ 15
Pharmacogenetics of Drug Metabolism: Historical Aspects 328
Genetic Polymorphisms of Individual Drug-Metabolizing -Genes 329
Keywords
Drug metabolism, Drug-metabolizing enzymes, Drug-metabolizing genes, Genetic
polymorphisms, Pharmacodynamics, Pharmacogenetics, Polymorphic enzyme
Key Points
• The goal of effective and safe therapy of many drugs is made difficult by large interpatient
variability in response and toxicity, and this problem is a substantial burden for patients, their
caretakers, and the health-care system.
• Pharmacogenetic tests that are most valuable are those for specific drugs for which the
prediction of activity or adverse effects is important and difficult to anticipate given our current
clinical tools and technologic capability.
• Although data from a variety of platforms documenting a wide range of genetic variability are
being accumulated rapidly and clinical genetic tests have been recommended or implemented for
drugs such as, irinotecan, and tamoxifen, there is still a great need for well-designed, prospective
clinical trials that test pharmacogenetic approaches versus standard practice.
(Robertson and Williams,2017, pp.).
Introduction
The safety and effectiveness of therapeutic drugs in patients’ treatment is difficult due to
the differences response and toxicology, resulting to significant burden for patients, care givers
and the health- care providers, e.g. for all major classes of drugs patients: may not respond or
respond only partially, experience adverse drug reactions when given standard doses, others such
as differences in pharmacokinetic (affecting drug concentrations) and pharmacodynamic
(affecting drug targets) contribute to this variable response. The potential causes for variable
drug efficacy and toxicity include a host of intrinsic and extrinsic factors, inherited differences in
drug-metabolizing enzymes, drug transporters, and drug targets of the interindividual differences
in drug disposition and response. Genetic factors are among factors that account for the
variability in drug disposition and effects (Robertson and Williams,2017, p.327).
2. Pharmacogenetics of drug transporters and drug targets: Common genetic polymorphisms
affecting pharmacokinetics via effects on drug metabolism and their clinical relevance:
The response to chronic administration for many drugs is determined by the area under
the plasma concentration time curve (AUC) during a dosing interval at steady state and a
measure of drug exposure. For an orally administered drug, the AUC PO is given by: AUC PO =
F PO ∗Dose PO /CL. The most important variants in drug metabolism are those that affect the
AUC by causing a change in either the oral bioavailability (F PO) or the apparent oral clearance
(CL). Changes in drug concentrations can vary by up to 600-fold between two individuals of the
same weight on the same drug dosage, other aspects of pharmacokinetics (e.g., absorption and
distribution) can potentially be controlled by genetic variation. Aspects that influence some drug
and metabolite clearance (elimination) are important for chronic dosing e.g. excretion by renal,
hepatobiliary, and other routes. Most of the drugs are eliminated primarily by metabolism via
enzymes located in the liver and the gut wall, metabolism is the most common and major cause
for variable drug response (Robertson and Williams,2017, p.328).
Two categories of metabolic reactions:
Phase I reactions (oxidation, hydrolysis, and reduction) result in relatively small
chemical changes that often make compounds more hydrophilic, facilitated by a wide
range of enzymes e.g. oxidoreductases, dehydrogenases and others, however, there
understanding the genetic influence on the activity of these enzymes is evolving because
there are few researches conducted on them. The pathway of phase I drug metabolism is
oxidation by hemeproteins called the cytochrome P450 (CYP) enzymes, situated in the
endoplasmic reticulum of hepatocytes and enterocytes, adverse drug reactions and drug
interactions metabolized by CYPs are major causes of morbidity and mortality that
compromise public health. In humans, there are 18 families of CYP genes, but only 8
enzymes that belong to the CYP1, CYP2, and CYP3 subfamilies are responsible for
xenobiotic and drug metabolism (Robertson and Williams,2017, p.328).
Phase II reactions involve acetylation, methylation, and conjugation with glucuronic
acid, amino acids, or inorganic sulfate. The main enzymes involved in these reactions
include UDP-glucuronyltransferases (UGTs), sulfotransferases, glutathione-S-
transferases, N-acetyltransferases (NATs), and methyltransferases. Metabolism in this
phase leads to more water-soluble molecules that are more easily eliminated by biliary or
renal elimination. Evidence shows that UGT-mediated conjugation an important route of
clearance for some commonly used drugs (Robertson and Williams,2017, p.328).
Pharmacogenetics of Drug Metabolism: Historical Aspects
In the early 1900’s, research Garrod, 1909 and Fox, 1932, presented discoveries of the
ideas that response to xenobiotics might be controlled by genetics and ethnic differences,
suggesting there is variable response to chemicals based on the individuality in man e.g. study
showed that some people are unable to taste phenylthiocarbamide while others taste it bitter, and
the frequency of nontasters varies among ethnic groups. Inheritance was suggested to contribute
to variation in drug response in an ethnic-dependence during World War II e.g. hemolytic crises
3. induced by primaquine or other chemically related antimalarial drugs are much more common in
African Americans than in Caucasians. The observation was explained by genetic defects
discovered in glucose-6-phosphate dehydrogenase. Individuals. Innovative discoveries showing
a link between deficiencies in drug metabolism and unexpected adverse drug effects were made
between the early 1950s and 1959, and encouraged further research into variable drug response,
called “pharmacogenetics.” Through pharmacogenetics the CYP2D6 and CYP2C19
polymorphisms enzyme was identified in the 1960s and 1970s. Many years after the differences
in phenotypes were discovered, the underlying molecular genetic causes of drug metabolism
deficiencies were explained through cloning of the genes—for example, CYP2D6 in 1988, NAT-
2 in 1991, TPMT in 1993, CYP2C19 in 1994. The discoveries from the human genome project
and technological advances in molecular biology, have led to captivating interest in inherited
differences of drug metabolism and response (Robertson and Williams,2017, p.328).
Genetic Polymorphisms of Individual Drug-Metabolizing Genes
These are examples of the several enzymes involved in the drug biosynthesis and
metabolic activation:
CYP1A2: Is the main clearance mechanism for clinically important drugs such as
caffeine, clozapine, and orhers.). The genetic polymorphisms influence CYP1A2 activity,
as measured by caffeine metabolism, varies widely (up to 70-fold) among subjects
Clozapine: is a prototypical atypical antipsychotic whose metabolism covaries with
CYP1A2 activity. clinical studies indicate an association between the CYP1A2∗1F allele
and enhanced clozapine clearance, e.g. increased dose requirement and
nonresponsiveness, particularly in smokers, and increased plasma concentrations and
adverse effects after discontinuation of smoking. and CYP1A2∗1C and CYP1A2∗1D
(−2467delT) appear to be associated with increased clozapine exposure and adverse
effects
Caffeine: CYP1A2 plays an established important role in caffeine metabolism. Caffeine
metabolism is one of the best markers of CYP1A2 activity available in vitro and in vivo
and has been used as an important tool to study the influence of genetic and nongenetic
factors influencing CYP1A2 function. The CYP1A2∗1F variant appears to increase the
clearance of caffeine in smokers. CYP1A2∗1F allele is associated with Increased risk of
recurrent pregnancy loss induced by caffeine, and decreased risk of nonfatal myocardial
infarction induced by caffeine. However, no genetically polymorphic site in the CYP1A2
gene can be used currently to predict the extensive interindividual variation in metabolic
phenotype between individuals, despite the identification of many variant alleles and
extensive resequencing efforts. Further studies are required to define the contribution of
the CYP1A2 genetic and including clinical response to drugs metabolized primarily by
this rout
CYP2B6: They play a minor role in human drug metabolism because they have none or
very low levels of CYP2B6 expression in human livers. Have shown these
polymorphisms alter drug exposure and in certain cases, drug response
4. Efavirenz: it is a nonnucleoside reverse transcriptase inhibitor–based therapy, often
preferred at initial therapy of HIV infection, but there is high interpatient variability in its
pharmacokinetics and clinical response at the usual therapeutic dose (600 mg/day oral
dose). A range of translational studies have consistently demonstrated that some of the
CYP2B6 genes by far are the most frequent variant associated with functional changes in
activity (40–60% in certain populations, with wide interethnic variability). Some are
highly dependent on the ethnic background of the population. However, there is not
sufficient knowledge and efficient tools to predict the large interindividual variability in
CYP2B6 activity with assurance
CYP2C8: This enzyme is important in the elimination of drugs used in the treatment of
diabetes (repaglinide), cancer (paclitaxel), antianemic (daprodustat), malaria
(amodiaquine and chloroquine), asthma (montelukast) and other
CYP2C9: The CYP2C9 enzyme is mainly expressed in the liver, drugs primarily
metabolized by CYP2C9 include oral anticoagulants (e.g., warfarin), oral
hypoglycaemics (e.g., tolbutamide) and others. This variability is associated with
difficulties in dose adjustment or with life-threatening adverse effects of drugs such as
warfarin and phenytoin. Genetic polymorphisms contribute greatly to influence its
activity
Warfarin: patients vary widely in their response to warfarin, necessitating a wide range
of doses (0.5–60 mg/day) to achieve optimal therapeutic anticoagulation responses.
Several interacting factors, including inherited differences in warfarin metabolism are
established as an important contributor to this variable response. Research have
demonstrated that genotype-driven approach has resulted to FDA approve change to a
warfarin label, that may cause an adoption of clinical pharmacogenetic testing before the
use of warfarin, and in general
Phenytoin: Phenytoin use for the treatment and prevention of seizures, difficult to dose
because of its low therapeutic index, which hinders its optimal and safe use.
CYP2C19: This an important enzyme it is expressed primarily in human liver, important
in the metabolism of widely used drugs such as several antidepressants, diazepam, and
others
(Robertson and Williams,2017, pp.329-342).
There are other genetic polymorphisms of individual drug-metabolizing genes they are:
Proton Pump Inhibitors, Clopidogrel, Cyclophosphamide, CYP2D6, Substrates, Tamoxifen,
Codeine, Antidepressants, CYP3A5, Tacrolimus, Vincristine, N-acetyltransferase 2, Isoniazid,
Thiopurine Methyltransferase, UDP-Glucuronosyltransferase(Robertson and Williams,2017,
pp.329-342).
Conclusions
Some drug-metabolizing enzymes are shown to cause large pharmacokinetic changes
through a variety of different mechanisms, those affected are have a dominant route of clearance
by a genetically polymorphic enzyme. The effects of such changes are most important in settings
where clinically important pharmacodynamic change results. Pharmacogenetic tests are
5. recommended to understand the activity and adverse effects of some specific drugs given our
current clinical tools and technologic capability. Even with some data documenting a wide range
of genetic variability, there is still a great need for well-designed, prospective clinical trials that
test pharmacogenetic approaches versus standard practice, also, needed is a translational value in
the simple, careful observation of clinical outlier phenotypic responses to drug therapy and in
research that attempts to identify pharmacokinetic, pharmacodynamic, and genetic mechanisms
underlying such variability (Robertson and Williams,2017, 343).
Reference.
Robertson. D and Williams G. H. (2017). Chapter 18: Pharmacogenetics of Drug
Metabolism _Clinical and
Translational Science: Principles of Human Research, pp. 327-345.Retrievevd from
https://www-clinicalkey-com.proxygw.wrlc.org/#!/content/book/3-s2.0-
B9780128021019000181