Presentation on

Pharmacogenomics

Submitted toDr. Sudipta SahaAsst. Professor

Submitted by:Pooja JoshiM.Pharm (Pharmacology) 2 sem

CONTENTS

Introduction Genetic polymorphism Genetic polymorphism influencing drug

disposition. Drug metabolism Polymorphism in drug transfer genes Polmorphism in drug target genes Applications Challenges of pharmacogenomics

Introduction

o Pharmacogenomics can be defined as the technology that analyzes how the genetic makeup of an individual affects his/her response to drugs.

o It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression or single nucleotide polymorphisms with pharmacokinetics and pharmacodynamics.

o Pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects.

o It attempts to eliminate the trial-and-error method of prescribing, allowing physicians to take into consideration their patient's genes, the functionality of these genes, and how this may affect the efficacy of the patient's current or future treatments.

Genetic Polymorphism

1. Single nucleotide polymorphisms (SNPs) changes in single nucleotide bases (A, C, G and

T).

…CTAGATACGAACTGCATC… …CTAGATACGGACTGCATC…

More than 14 million SNPs have been identified in the human genome. More than 60,000 SNPs are located in the coding regions of the genes

2. Structural variation:o changes affecting chunks of DNA which can

consequently alter the structure of the entire chromosome. Structural variation can happen in a number of ways;for example:

Copy number variation (CNV): when there is an increase or decrease in the amount

of DNA. This can be due to:deletion: where an entire block of DNA is

missinginsertion: where a block of DNA is added induplication: where there are additional copies of

a section of DNA.

Inversion: when a chromosome breaks in two places and the resulting piece of DNA is reversed and reinserted back into the chromosome (the opposite way round).

Translocation: when genetic material is exchanged between two different chromosomes.

GENETIC POLYMORPHISMS INFLUENCING DRUG DISPOSITION

Drug Metabolism

1. CYP2C9 CYP2C9 is the major CYP2C gene product that

catalyzes oxidation of the substrates tolbutamide, diclofenac, and warfarin in human liver microsomes.

2. CYP2C19 CYP2C19 plays an important role in the

metabolism of several drugs including omeprazole, lansoprazole, diazepam, and proguanil.

3. CYP2D6 CYP2D6 mediates the oxidation of many currently

prescribed drugs including antidepressants, neuroleptics, , beta-adrenoreceptor blockers, and antiarrhythmics.

4. CYP2A6 CYP2A6 is an important hepatic P450 that can

activate many different pre-carcinogens, including N-nitrosodiethylamine, aflatoxin B1, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

5. CYP3A4 CYP3A4 metabolizes a vast array of clinically,

physiologically, and toxicologically important compounds.

6. N-Acetyltransferase 2 N-Acetyltransferase 2 (NAT2) plays an important

role in the metabolism and detoxification of many arylamine and hydrazine drugs such as isoniazid and sulphonamide.

7. Thiopurine S-Metyltransferase Thiopurine S-metyltransferase (TPMT) catalyzes

the metabolism of important drugs such as 6-mercaptopurine, 6-thioguanine and azathioprine.

8. Dihydropyrimidine Dehydrogenase Dihydropyrimidine dehydrogenase protein (DPD) degrades more than 80% of administered 5-fluorouracil (5-FU) thereby regulating its pharmacokinetics ,clinical efficacy and cytotoxicity.

9. Aldehyde Dehydrogenase 2 Alcohol metabolism is a biological determinant

that can significantly affect drinking behavior and alcohol related organ damage. Aldehyde dehydrogenase (ALDH), particularly mitochondrial aldehyde dehydrogenase 2 (ALDH2), plays an important role in acetaldehyde detoxication.

GENE DRUGS & SUBSTARTES

CYP2C9 Tolbutamide, diclofenac, warfarin

CYP2C19 Omeprazole, lansoprazole, diazepam, proguanil

CYP2D6 Antidepressants, codeine, b-blockers

CYP2A6 Coumarin

CYP3A4 Nifedipine

NAT2 Isoniazid, sulphonamide

TPMT 6 Mercaptopurine, 6-thioguanine, azathioprine

DPYD 5 Fluorouracil

ALDH2 Acetaldehyde

AmpliChip CYP450 Test

o The test aims to find the specific gene types of the patient that will determine how he or she metabolizes certain medicines, therefore guides the doctors to prescribe medicine for best effectiveness and least side effects.

o The AmpliChip CYP450 Test uses micro array technology from Affymetrix (Genechip) to determine the genotype of the patient in terms of two cytochrome P450 enzymes: 2D6 and 2C19.

POLYMORPHISMS IN DRUG TRANSPOTERS GENE

o P-glycoprotein is one of the most recognized of the drug transport proteins that exhibit genetic polymorphism.

o P-glycoprotein is an energy-dependent transmembrane efflux pump encoded by the ABCB1 gene (also known as the multidrug resistance 1 gene), which is a member of the ATP-binding cassette (ABC) transporter superfamily.

o At least 50 SNPs have been identified in the promoter and exon regions of the ABCB1 gene.

o  Increased ABCB1 expression may limit the ability of some antiepileptic agents to penetrate the blood brain barrier, thus leading to drug resistant epilepsy.

POLYMORPHISMS IN DRUG TARGET GENES

beta2-adrenoceptor o Genetic factors controlling b2-adrenoceptor (b2-AR)

function may be very important determinants of response to bronchodilator therapy for asthma.

o Nine polymorphisms in the beta2-AR gene have been described, two of which were more frequent and gave rise to amino acid changes in the putative extracellular amino-terminus region of the gene: Arg16Gly and Gln27Glu.

o Dose–response relationships in individuals with different beta2-AR polymorphisms may help to clarify the precise role of these polymorphisms in determining the range of potential response to b2- adrenergic agonists.

The dopamine D4 receptor gene is an example of a receptor gene linked to drug toxicity. 

o Tardive dyskinesia is a debilitating and potentially irreversible adverse effect that occurs in up 25% of patients treated with first-generation antipsychotics, such as thioridazine or haloperidol.

o Antipsychotics antagonize dopamine D2 receptors to produce their antipsychotic effects. Genes encoding for the dopamine  D3 and D4 receptors have been implicated in the risk for tardive dyskinesia

APPLICATION o Improve drug safety, and reduce ADRs;o Tailor treatments to meet patients' unique

genetic pre-disposition, identifying optimal dosing;

o Improve drug discovery targeted to human disease;

o Improve proof of principle for efficacy trialso Pharmacogenomics may be applied to several

areas of medicine, including Pain Management, Cardiology, Oncology, and Psychiatry.

o  Pharmacogenomics can be used to determine the cause of death in drug-related deaths where no findings emerge using autopsy.

o In cardiovascular disorders, the main concern is response to drugs including warfarin, clopidogrel, beta blockers & statins.

Challenges of pharmacogenomics Although pharmacogenomics is likely to be an

important part of future medical care, there are many obstacles to overcome before it becomes routine:

o It is relatively rare for a particular drug response to be affected by a single genetic variant.

o A particular genetic variant may increase the likelihood of an adverse reaction but it will not guarantee it.

o As a result some people with the variant may not experience an adverse reaction to a drug.

o There are often a large number of interacting genetic and environmental factors that may influence the response to a drug.

o Even when associations between a genetic variant and a drug response have been clearly demonstrated, suitable tests still have to be developed and proved to be effective in clinical trials.

o A test that has succeeded in a clinical trial still has to be shown to be useful and cost-effective in a healthcare setting.

o Regulatory agencies will have to consider how they assess and license pharmacogenetic products.

o Health services will have to adjust to new ways of deciding the best drug to give to an individual.