Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
Genetic polymorphism in drug transport and drug targets.pavithra vinayak
Genetic polymorphism in drug transport and targets.--pharmacogenetics
DRUG TRANSPORTER
Two types of transporter :
•ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family. Associated with multidrug resistance (MDR) of tumor cells causing treatment failure in cancer.
•Solute Carrier (SLC) – Transport varieties of solute include both charged or uncharged
P-glycoprotein
• ATP binding cassette subfamily B member- 1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Mechanism of Pglycoprotein
Substrate bind to P-gp form the inner leaflet of the membrane
ATP binds at the inner side of the protein
ATP is hydrolyzed to produce ADP and energy
Description on definition of pharmacogenetics, role of pharmacogenetics in drug response, role of polymorphism in drug metabolism, drug transporters and drug targets.
Population pharmacokinetics is the study of the sources and correlates of variability in drug concentrations among individuals who are the target patient population receiving clinically relevant doses of a drug of interest
breif notes on what is pharmacoepidemiology, why do we need pharmacoepidemiology, whats is its aim and its main applications, advantages and disadvantages
GENETIC POLYMORPHISM IN DRUG METABOLISM.pptxAmeena Kadar
Genetic Polymorphism is one of the factors that affects the Drug metabolism. Cytochrome P - 450, one of the prominent group of metabolizing enzymes. In this ppt, genetic polymorphism of cytochrome p 450 is discussed.
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Nomograms and tabulations in design of dosage regimens pavithra vinayak
Nomograms and tabulations in the design of dosage regimens --- NOMOGRAM IN UREMIC PATIENTS: NOMOGRAM FOR RELATIONSHIP BETWEEN CREATININE CLEARANCE AND ELIMINATION RATE CONSTANT FOR FOUR DRUGS clinical pharmacokinetics and therapeutic drug monitoring ---fifth PharmD notes
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
The topic of pharmacogenetics and pharmacokinetics will be explored in this presentation, with a focus on how the way drugs are metabolized can be affected by genetics, and how this information can be used to personalize drug therapy. Topics such as drug response, drug metabolism, drug-drug interactions, and adverse drug reactions will be covered. The importance of pharmacokinetic profiling and therapeutic drug monitoring in ensuring drug safety and effectiveness will also be discussed. Valuable insights into the field of pharmacology and its potential to revolutionize patient care will be provided, making this presentation of interest to healthcare professionals, researchers, and those who wish to learn more about personalized medicine. The world of pharmacogenomics and genomic medicine will be delved into.
The presentation will also highlight the importance of pharmacodynamics and pharmacokinetics in drug development and clinical pharmacology.
By the end of this presentation, you will have a better understanding of the underlying principles of pharmacogenetics and pharmacokinetics and how they can be applied to optimize drug therapy for individual patients. This knowledge is essential for anyone involved in healthcare and drug development, as it has the potential to improve treatment outcomes and reduce adverse drug reactions.
breif notes on what is pharmacoepidemiology, why do we need pharmacoepidemiology, whats is its aim and its main applications, advantages and disadvantages
GENETIC POLYMORPHISM IN DRUG METABOLISM.pptxAmeena Kadar
Genetic Polymorphism is one of the factors that affects the Drug metabolism. Cytochrome P - 450, one of the prominent group of metabolizing enzymes. In this ppt, genetic polymorphism of cytochrome p 450 is discussed.
Bayesian theory was developed to improve forecast accuracy by combining subjective prediction with improvement from newly collected data.
Bayesian probability is used to improve forecasting in medicine.
Bayesian theory provides a method to weigh the prior information (e.g. physical diagnosis) and new information (e.g. results from laboratory tests) to estimate a new probability for predicting the disease.
conversion from INTRAVENOUS TO ORAL DOSING----- design of dosage regimenpavithra vinayak
conversion from INTRAVENOUS TO ORAL DOSING----- TYPES OF IV TO PO THERAPY CONVERSIONS: MEDICATIONS INCLUDED IN AN IV TO PO CONVERSION PROGRAM: SELECTION OF PATIENTS FOR IV TO PO THERAPY CONVERSION: design of dosage regimen--clinical pharmacokinetics and therapeutic drug monitoring-- fifth pharm D notes
Nomograms and tabulations in design of dosage regimens pavithra vinayak
Nomograms and tabulations in the design of dosage regimens --- NOMOGRAM IN UREMIC PATIENTS: NOMOGRAM FOR RELATIONSHIP BETWEEN CREATININE CLEARANCE AND ELIMINATION RATE CONSTANT FOR FOUR DRUGS clinical pharmacokinetics and therapeutic drug monitoring ---fifth PharmD notes
Clinical pharmacokinetics and its application--
1)definition
2) APPLICATIONS OF CLINICAL PHARMACOKINETICS
Design of dosage regimens:
a) Nomograms and Tabulations in designing dosage regimen,
b) Conversion from intravenous to oral dosing,
c) Determination of dose and dosing intervals,
d) Drug dosing in the elderly and pediatrics and obese patients.
Pharmacokinetics of Drug Interaction:
a) Pharmacokinetic drug interactions
b) Inhibition and Induction of Drug metabolism
c) Inhibition of Biliary Excretion.
Therapeutic Drug monitoring:
a) Introduction
b) Individualization of drug dosage regimen (Variability – Genetic, Age and Weight, disease, Interacting drugs).
c) Indications for TDM. Protocol for TDM.
d) Pharmacokinetic/Pharmacodynamic Correlation in drug therapy.
e) TDM of drugs used in the following disease conditions: cardiovascular disease, Seizure disorders, Psychiatric conditions, and Organ transplantations
Dosage adjustment in Renal and Hepatic Disease.
a. Renal impairment
b. Pharmacokinetic considerations
c. General approach for dosage adjustment in renal disease.
d. Measurement of Glomerular Filtration rate and creatinine clearance.
e. Dosage adjustment for uremic patients.
f. Extracorporeal removal of drugs.
g. Effect of Hepatic disease on pharmacokinetics.
Population Pharmacokinetics.
a) Introduction to Bayesian Theory.
b) Adaptive method or Dosing with feedback.
c) Analysis of Population pharmacokinetic Data
The topic of pharmacogenetics and pharmacokinetics will be explored in this presentation, with a focus on how the way drugs are metabolized can be affected by genetics, and how this information can be used to personalize drug therapy. Topics such as drug response, drug metabolism, drug-drug interactions, and adverse drug reactions will be covered. The importance of pharmacokinetic profiling and therapeutic drug monitoring in ensuring drug safety and effectiveness will also be discussed. Valuable insights into the field of pharmacology and its potential to revolutionize patient care will be provided, making this presentation of interest to healthcare professionals, researchers, and those who wish to learn more about personalized medicine. The world of pharmacogenomics and genomic medicine will be delved into.
The presentation will also highlight the importance of pharmacodynamics and pharmacokinetics in drug development and clinical pharmacology.
By the end of this presentation, you will have a better understanding of the underlying principles of pharmacogenetics and pharmacokinetics and how they can be applied to optimize drug therapy for individual patients. This knowledge is essential for anyone involved in healthcare and drug development, as it has the potential to improve treatment outcomes and reduce adverse drug reactions.
general information regarding single nucleotide polymorphism.
A Single Nucleotide Polymorphisms (SNP), pronounced “snip,” is a genetic variation when a single nucleotide (i.e., A, T, C, or G) is altered and kept through heredity.
DNA sequence variations are sometimes described as mutations and sometimes as polymorphisms. A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population.
Polymorphic sequence variants usually do not cause overt debilitating diseases. Many are found outside of genes and are completely neutral in effect. Others may be found within genes, but may influence characteristics such as height and hair colour rather than characteristics of medical importance.
However, polymorphic sequence variation does contribute to disease susceptibility and can also influence drug responses (Single Nucleotide Polymorphisms).
It promotes diversity and persists over many generations because no single form has an overall advantage or disadvantage over the others in terms of natural selection.
It is originally used to describe visible forms of genes, but now used to include cryptic modes such as blood types, which require a blood test to decode.
In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to generally be considered polymorphic.
Gene polymorphisms can occur in any region of the genome.
The majority of polymorphisms are silent, meaning they do not alter the function or expression of a gene.
Some polymorphism is visible. For example, in dogs the E locus, can have any of five different alleles, known as E, Em, Eg, Eh, and e. Varying combinations of these alleles contribute to the pigmentation and patterns seen in dog coats.
Human blood groups is also a polymorphic effect.
Human skin color is influenced by an intergenic DNA polymorphism regulating transcription of the nearby BNC2 pigmentation gene.
Genomics is impacting all areas of medicine. In transfusion medicine, DNA-based genotyping is being used as an alternative to serological antibody-based methods.
Single nucleotide changes (SNP's) in the respective genes are responsible for most antigenic polymorphisms.
Validated by comparison with antibody-based typing.
Provide the patient’s comprehensive extended blood group profile as part of their medical record by the growth of whole-genome sequencing (WGS).
pharmacogenomics helps to improve healthcare sector by providing information about variability among genes for a particular class of drug hence reduces adverse drug reactions.
The Emerging Role of Pharmacists in Public Health.pptxDr. Ankit Gaur
The Emerging Role of Pharmacists in Public Health: Opportunities and Challenges
General system theory, steven's system model, Pharmacists in india, Disaster management and emergency care, rational use of medicine, RNTCP programme. National Aids Control Programme.
This presentation is about Stress and its impact on health. I have tried to cover everything related to it, stressors, coping mechanisms, tools, types etc.
Gastro esophageal Reflux Disease (GERD) and its managementDr. Ankit Gaur
In this presentation I have tried to explain in brief about gastro esophageal Reflux Disease (GERD), its etiology, risk factors, diagnosis, and its management via pharmacotherapy.
In this presentation I have tried to discuss in brief about obsessive compulsive disorder and its treatment both pharmacological and non pharmacological.
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In this presentation I have tried to explain the types, etiology, pathophysiology of respiratory tract infections such as bronchitis, pnemonia, otitis media, sinusitis, pharyngitis, and their treatment
In this presentation I have tried to explain in brief about the dosage adjustment in renal disorders, how to carry out this process and the important formulae which are used in it.
In this presentation i have tried to explain in brief about nomograms and their applications, the general approach to individualise doage regimen by using pharmacokinetic data
In this presentation I have tried to explain in detail about tablets, their different types, ingredients which are used to prepare them, and the procedure to prepare them as well. This presentation is very useful for pharmacy students.
In this presentation i have tried to explain in details about the Total Parenteral Nutrition (TPN) , what is it, who needs it, and how to prepare it and the necessary procedure with instructions. It is very useful for the individuals from Nutrition, Nursing, Pharmacists, and Medical background.
in this presentation i have tried to briefly discuss about diuretics (water pills), their classification, mechanism of action, pharmacokinetics and pharmacodynamics of these drugs
In this presentation i have tried to explain in brief about CPR, how and when it has to be done and the important things to be kept in mind while doing it. This ppt is very helpful for every individual who is looking for the info regarding CPR.
In this presentation i have tried to explain in detail about the nux vomica and khurchi bark. This presentation is useful for the individuals who are looking for information on this topic especially for those students who are studying Pharmacognosy.
In this presentation i have tried to explain in detail about the measurements of the outcomes which are used in epidemiology such as prevalence, incidence, fatality rate, crude death rate etc.
In this presentation i tried to explain in detail about cohort studies, their types, how to conduct them, their outcomes, and how to calculate sample size of these studies.
In this presentation i have tried to thoroughly discuss about the concept of Drug induced kidney disease or injury, the mechanism behind it, its classification and how to access it.
Drug induced liver injury (DILI) and HepatotoxicityDr. Ankit Gaur
In this presentation I have tried to explain the defination, Mechanism of drug induced liver injury (DILI) and hepatotoxicity with the help of few examples.
India Clinical Trials Market: Industry Size and Growth Trends [2030] Analyzed...Kumar Satyam
According to TechSci Research report, "India Clinical Trials Market- By Region, Competition, Forecast & Opportunities, 2030F," the India Clinical Trials Market was valued at USD 2.05 billion in 2024 and is projected to grow at a compound annual growth rate (CAGR) of 8.64% through 2030. The market is driven by a variety of factors, making India an attractive destination for pharmaceutical companies and researchers. India's vast and diverse patient population, cost-effective operational environment, and a large pool of skilled medical professionals contribute significantly to the market's growth. Additionally, increasing government support in streamlining regulations and the growing prevalence of lifestyle diseases further propel the clinical trials market.
Growing Prevalence of Lifestyle Diseases
The rising incidence of lifestyle diseases such as diabetes, cardiovascular diseases, and cancer is a major trend driving the clinical trials market in India. These conditions necessitate the development and testing of new treatment methods, creating a robust demand for clinical trials. The increasing burden of these diseases highlights the need for innovative therapies and underscores the importance of India as a key player in global clinical research.
Navigating Challenges: Mental Health, Legislation, and the Prison System in B...Guillermo Rivera
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CHAPTER 1 SEMESTER V PREVENTIVE-PEDIATRICS.pdfSachin Sharma
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Deep Leg Vein Thrombosis (DVT): Meaning, Causes, Symptoms, Treatment, and Mor...The Lifesciences Magazine
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One of the most developed cities of India, the city of Chennai is the capital of Tamilnadu and many people from different parts of India come here to earn their bread and butter. Being a metropolitan, the city is filled with towering building and beaches but the sad part as with almost every Indian city
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According to Chris Mouchabhani, Managing Partner at M Capital Group, “Despite all economic scenarios that one may consider, beyond overall economic shocks, medical technology should remain one of the most promising and robust sectors over the short to medium term and well beyond 2028.”
There is a movement towards home-based care for the elderly, next generation scanning and MRI devices, wearable technology, artificial intelligence incorporation, and online connectivity. Experts also see a focus on predictive, preventive, personalized, participatory, and precision medicine, with rising levels of integration of home care and technological innovation.
The average cost of treatment has been rising across the board, creating additional financial burdens to governments, healthcare providers and insurance companies. According to MCG, cost-per-inpatient-stay in the United States alone rose on average annually by over 13% between 2014 to 2021, leading MedTech to focus research efforts on optimized medical equipment at lower price points, whilst emphasizing portability and ease of use. Namely, 46% of the 1,008 medical technology companies in the 2021 MedTech Innovator (“MTI”) database are focusing on prevention, wellness, detection, or diagnosis, signaling a clear push for preventive care to also tackle costs.
In addition, there has also been a lasting impact on consumer and medical demand for home care, supported by the pandemic. Lockdowns, closure of care facilities, and healthcare systems subjected to capacity pressure, accelerated demand away from traditional inpatient care. Now, outpatient care solutions are driving industry production, with nearly 70% of recent diagnostics start-up companies producing products in areas such as ambulatory clinics, at-home care, and self-administered diagnostics.
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Empowering ACOs: Leveraging Quality Management Tools for MIPS and BeyondHealth Catalyst
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2. INTRODUCTION
Pharmacogenetics involves the search for genetic variations that lead to
interindividual differences in drug response. The term pharmacogenetics
often is used interchangeably with the term pharmacogenomics.
However, pharmacogenetics generally refers to monogenetic variants that
affect drug response, whereas pharmacogenomics refers to the entire
spectrum of genes that interact to determine drug efficacy and safety.
3. NEED FOR PHARMACOGENETICS
The goals of pharmacogenetics are to optimize drug therapy and limit
drug toxicity based on an individual’s genetic profile.
Thus, pharmacogenetics aims to use genetic information to choose a drug,
drug dose, and treatment duration that will have the greatest likelihood of
achieving therapeutic outcomes with the least potential for harm in a
given patient.
5. A gene is a series of codons that specifies a particular protein.
Genes contain several regions: exons that encode for the final protein,
introns that consist of intervening noncoding regions, and regulatory
regions that control gene transcription. In most cases, an individual
carries two alleles, one from each parent, at each gene locus.
An allele is defined as the sequence of nucleic acid bases at a given gene
chromosomal locus. Two identical alleles make up a homozygous
genotype. Two different alleles make up a heterozygous genotype. The
phenotype refers to the outward expression of the genotype.
6. Polymorphisms are defined as variations that occur at a frequency of at
least 1% in the human population.
Single nucleotide polymorphisms (SNPs; pronounced “snips”) are the
most common genetic variations in human DNA, occurring
approximately once in every 100 to 300 base pairs.
To date more than four million SNPs have been mapped in the human
genome.
SNPs are single-base differences that exist between individuals.
Nucleotide substitution results in two possible alleles.
7.
8. A SNP may change the codon resulting in amino acid substitution, which may
or may not alter the amount or function of the encoded protein.
SNPs such as this that result in amino acid substitution are referred to as
nonsynonymous. Nonsynonymous SNPs usually are designated by the amino
acids and codon involved. For example, Arg16Gly or Arg16→Gly indicates
that glycine is substituted for arginine at codon 16.
SNPs that do not result in amino acid substitution are called synonymous.
Synonymous SNPs usually are abbreviated based on the nucleotides involved
and the nucleotide base position. For example, A1166C or A1166→C
indicates that cytosine is substituted for adenine at nucleotide position 1166 of
a given gene region.
9. Insertion–deletion polymorphisms, in which a nucleotide or nucleotide sequence either is
added to or deleted from a DNA sequence
Tandem repeats, in which a nucleotide sequence repeats in tandem (e.g., if “AG” is the
nucleotide repeat unit, “AGAGAGAGAG” is a five-tandem repeat)
Frameshift mutation, in which there is an insertion/deletion polymorphism and the number
of nucleotides added or lost is not a multiple of three, resulting in disruption of the gene’s
reading frame
Defective splicing, in which an internal polypeptide segment is abnormally removed, and the
ends of the remaining polypeptide chain are joined
Aberrant splice site, in which processing of the protein occurs at an alternate site
Premature stop codon polymorphisms, in which there is premature termination of the
polypeptide chain by a stop codon (specific sequence of three nucleotides that do not code for
an amino acid but rather specify polypeptide chain termination)
10. SNPs may occur in exon, intron, or regulatory regions of a gene.
Those occurring in exon regions may alter the function of a protein, whereas
those in regulatory regions may alter the amount of protein that is produced.
Variations in the intron region often are silent unless they affect intron
splicing. Multiple SNPs may be in linkage disequilibrium with each other,
meaning that two or more SNPs are inherited together more frequently than
expected based on chance alone.
For example, if two SNPs, A46T and G72C, are possible in a given gene and
if a T at position 46 always occurs with a C at position 72, the two SNPs are
said to be in complete linkage disequilibrium. A set of SNPs that are inherited
together is called a haplotype.
11. DRUG TARGETS
Genetic polymorphisms occur commonly for drug target proteins,
including receptors, enzymes, ion channels, and intracellular
signaling proteins.
Drug target genes may work in concert with genes that affect
pharmacokinetic properties to contribute to overall drug response.
12.
13. RECEPTOR GENOTYPES AND
DRUG RESPONSE
β1-Receptors are located in the heart and kidney, where they are
involved in the regulation of heart rate, cardiac contractility, and
blood pressure. Two common nonsynonymous SNPs in the β1-
receptor gene are located at codons 49 (Ser→Gly) and 389
(Arg→Gly).
The influence of the β1-receptor gene on blood pressure response to
β1-receptor blockade with metoprolol.
Hypertensive patients who were homozygous for both the Ser49 and
Arg389 alleles had greater reductions in diastolic blood pressure
with metoprolol monotherapy compared with carriers of the Gly49
and/or Gly389 alleles.
14. β2-Receptors are located on bronchial smooth muscle cells, where they
mediate bronchodilation upon exposure to the β2-receptor agonists.
Inhaled β2-agonists are the most effective agents for acute reversal of
bronchospasm; however, the magnitude of their effects varies substantially
among asthmatic patients.
More than 11 SNPs have been identified in the β2-receptor gene, three of
which occur frequently and result in amino acid changes.
Two common nonsynonymous SNPs are found in the gene’s coding block
region, at codons 16 and 27, and a third occurs upstream from the coding
block in the gene’s promoter region.
15.
16. ENZYME GENES AND DRUG
RESPONSE
Vitamin K epoxide reductase (VKOR) is an example of an
enzyme with genetic contributions to drug response.
Warfarin exerts its anticoagulant effects by inhibiting VKOR, thus
preventing carboxylation of clotting factors II, VII, IX, and X.
The vitamin K epoxide reductase complex subunit-1 gene
(VKORC1) encodes for VKOR.
Mutations in the VKORC1 coding region cause rare cases of
warfarin resistance.
Carriers of these mutations either require exceptionally high
warfarin doses (>100 mg/wk) to achieve effective anticoagulation
or fail to respond to any dose of warfarin.
17. Haplotype
Name
Type Ethnic groups
1. VKORC1*1 Wild Reference sequence
AY587020
High frequencies
in populations of
African origin
2. VKORC1*2
(H1 & H2)
Variant A allele at position
3673 and a T allele at
position 6484 of
AY587020
Europeans 42%,
Chinese 95%,
African
Americans 14%
3. VKORC1*3
(H7,H8 & H9)
Variant A allele at position
9041 (homozygous)
heterozygous or
homozygous for the G
allele
African
population=
Caucasians
4. VKORC1*4
(H7,H8 & H9)
Variant position 9041
18. GENES FOR INTRACELLULAR SIGNALING
PROTEINS, ION CHANNELS, AND DRUG RESPONSE
Cellular responses to many drugs are mediated through GTPbinding proteins,
also called G proteins.
19. Disturbances in G-protein–mediated signal transduction have been implicated
in the response to antidepressant drugs.
A common SNP (C825T) occurs in the gene for the inhibitory G (Gi) protein
β3-subunit and has been associated with enhanced intracellular signal
transduction.
The TT genotype has been correlated with greater improvement in depression
symptoms among patients treated with either a tricyclic antidepressant or
serotonin reuptake inhibitor, implying that the Gi protein β3-subunit gene may
have a role in therapeutic decisions for depression management.
20. The epithelial sodium channel (ENaC) is an example of an ion channel with
genetic contributions to drug response.
The ENaC is located in the distal renal tubule and collecting duct of the
nephron, where it serves as the final site for sodium reabsorption.
The channel is composed of α-, β-, and γ-subunits. Mutations in the β- or γ-
subunit cause excessive sodium reabsorption and an inherited form of
hypertension called Liddle syndrome.
The more common variant Thr594Met occurs exclusively in blacks and is
associated with high blood pressure in this population.