GENETIC POLYMORPHISM IN DRUG METABOLISM.pptx

GENETIC POLYMORPHISM IN DRUG METABOLISM.pptx

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  GENETIC POLYMORPHISM INDRUG METABOLISM AMEENA KADAR K A SECOND SEM M PHARM DEPT. OF PHARMACY PRACTICE SANJO COLLEGE OF PHARMACEUTICAL STUDIES
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  PHARMACOGNETICS  The term"pharmacogenetics" was first coined by Friedrich Vogel in 1959, who defined it as the "study of the role of genetics in drug response."  It is one of the most rapidly growing areas and is becoming increasingly important in clinical pharmacy.  The pharmacogenetics of drug-metabolizing enzymes is a prominent focus of this field, because genetic makeup is responsible for a significant portion of drug-induced toxicity; many drugs are metabolized by enzymes that are encoded by polymorphically expressed genes. 2
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  3  Pharmacogenetics isthe study of the genetic basis of individual patient variability in the response to drug therapy. It has been defined as the study of variability in drug response due to heredity  Pharmacogenetics allows for individualization of drug therapy.  Pharmacogenomics is closely related to pharmacogenetics and is considered to be an equivalent or overlapping field.  Pharmacogenomics involves study of the role of genes and their genetic variations (DNA, RNA level) in the molecular basis of disease and the resulting pharmacologic impact of drugs on that disease.
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  4  Pharmacogenetic =pharma + genetic  Pharma - the Greek word ie ; pharmacon related to drugs  Genetic - related to genes or genomes.  Pharmacogenetic studies have also allowed us to better understand the pharmacology of medications used to treat neurologic & psychiatric disorders.  Pharmacogenetic focuses on the influence of single genes on drug response.  Ultimately, the goal of pharmacogenetics is to predict a patient’s genetic response to a specific drug as a means of delivering the best possible medical treatment.  By predicting the drug response of an individual, it will be possible to increase the success of therapies and reduce the incidence of adverse side effects.
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  APPLICATIONS OF PHARMACOGENETICS 5 1.Pharmacogenetics assays: Providing an assay for clinical assessment of a patient’s probable response to a drug is a major challenge in pharmacogenetics. It includes; • Improvement in a medically important response • Limited false positives (efficacy-based assay) • Limited false negatives (safety-based assay) • Interpretable and clinically useful results • Clinically validated results adequate for regulatory acceptance. 2. Pharmacogenetic Techniques
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  6 GENETIC POLYMORPHISM INDRUG METABOLISM  Genetic polymorphism is the variations in DNA sequences. This explain some of the variability in drug metabolizing enzyme activities which contribute to,  Alteration in drug response  Impact patient’s response to drug therapy  Several extensively studied SNPs (single nucleotide polymorphism) including the genes encoding for : 1. Glucose-6-phosphate dehydrogenase 2. N- acetyl transferase 3. The superfamily of Cytochrome P-450 (CYP) iso-enzymes.
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  CYTOCHROME P- 450ISOENZYMES 7  Many hepatic cytochrome P–450 enzymes play an important role in the oxidative biotransformation of numerous drugs and other foreign compounds, and of many endogenous substrates.  In humans more than 20 different iso-enzymes of cytochrome P- 450 responsible for the hepatic metabolism of drugs, have been identified.  They are classified into families and sub families on the basis of the degree of amino acid similarity.  Cytochrome P450 isoenzymes are regulated by both genetic and envi- ronmental factors.  Of particular interest is genetic polymorphism in drug oxidation.
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  8  Two geneticpolymorphisms in drug oxidation are well known, the sparteine/debrisoquine (CYP2D6) polymorphism and the mephenytoin oxidation (CYP2C19) polymorphism.  As a result of these polymorphisms, two phenotypes exist in the population, poor and extensive metabolizers.  Poor metabolizers may be prone to adverse reactions towards drugs with a narrow therapeutic range.  In extensive metabolizers clinically significant drug interactions between drugs metabolized by the same isoenzyme can occur.  Most oxidative processes take place in liver microsomes, a cellular fraction derived from the endoplasmic reticulum, and are catalyzed by mono- oxygenase enzymes known as mixed- function oxidases.
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  9  The terminaloxidizing enzyme is cytochrome P-450, a hemoprotein.  The term "P450" refers to the ability of the reduced (ferrous) form of the hemoprotein to react with carbon monoxide, yielding a complex with an absorption peak at 450 nm.  The term "Cytochrome P-450" refers not to one enzyme: more than 20 different P-450 isoenzymes have been identified in humans.  P-450 isoenzymes are grouped in families within which the amino acid se- quence homology is higher than 36%; they are designated by an Arabic number.  The majority of P-450 isoenzymes involved in drug metabolism belong to the CYP1, CYP2 and CYP3 families.  Each P-450 family is further divided into subfamilies, designated by capital letters, which contain proteins that share more than 75% amino acid sequence homology.
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  10  A secondArabic number is used for the individual isoenzymes.  Cytochrome P – isoenzymes in Humans  CYP1A2, CYP2D6, CYP3A4 and CYP2C19 are important isoenzymes in regard to drug metabolism in humans.  Different isoenzymes can be involved in the various steps of the metabolic pathway of a drug.
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  11  A particularstep is often catalyzed by one isoenzyme, but in some cases several isoenzymes can be involved.  Imipramine e.g. is hydroxylated by a single isoenzyme, CYP2D6, but is N- de-methylated by at least three different isoenzymes (CYP1A2, CYP2C19, CYP3A4).
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  12  Drugs assubstrates of specific Cytochrome P-450 isoenzymes
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  13 GENETIC FACTORS INFLUENCINGBIOTRANSFORMATION  It is known that interindividual differences in drug metabolism are largely under genetic control.  For drugs such as phenylbutazone, nortriptyline and dicoumarol, important differences in elimination rate can be seen within each pair of fraternal twins, whereas within each pair of identical twins elimination rates are quite similar.  Biotransformation is often under polygenetic control, and frequency distribution plots of metabolic parameters usually yield continuous, uni- modal curves.  For some drugs, however, metabolism is under monogenetic control and shows a bimodal distribution, with genetic polymorphism in the population.
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  14  Genetic polymorphismhas first been described for a biotransformation process which is not catalyzed by a cytochrome P-450 isoenzyme, the N- acetylation of isoniazide and of a number of other drugs (e.g. procainamide, hydralazine, dapsone, sulfadimidine).  Genetic polymorphism was later also recognized for drug oxidations, and has, up until now, been described for CYP2D6 and CYP2C19. The CYP2D6 polymorphism  This is often called the debrisoquine/sparteine polymorphism, for the two classical probes used to study this polymorphism.  Because in some countries debrisoquine and sparteine are not available, dextromethorphan, a commonly used cough suppressant drug, is used to determine the CYP2D6 phenotype of an individual.
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  15  CYP2D6 isprimarily expressed in the liver.  It is also highly expressed in areas of the central nervous system, including substantia nigra.  CYP2D6 is a 50-KD microsomal enzymes that metabolizes at least 25 different drugs including,  Anti-hypertensive agents  β-blockers  Anti-arrhythmic drugs  Anti-depressants
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  16 CYP2C9 Genes  TheCYP2C9 genes provides instructions for making an enzymes that is found in a cell structure called the endoplasmic reticulum which is involved in protein processing & transport.  They breakdown compounds including steroid hormones & fatty acids.  They play a major role in breaking down the drug Warfarin, which thin the blood & prevent blood clots from forming.  This enzyme also assists in metabolizing other drugs such as Ibuprofen, which reduces inflammation.
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  17 CYP1A2 Genes  Anotherisoenzyme, which metabolizes 5% of randomly selected drugs.  The protein encoded by this genes localizes to the endoplasmic reticulum & its expression is induced by some polycyclic aromatic hydrocarbon, some of which are found in cigarette smoke.  It is able to metabolize some PAHs to carcinogenic intermediates.  Other xenobiotic substrates for this enzymes include caffeine, aflatoxin B1 & acetaminophen.
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  18 CYPC19 Genes  TheCYP2C19 enzyme play a role in the processing or metabolizing of at least 10% of commonly prescribed drugs. Eg : clopidogrel  It is an anti-platelet drugs which means that it prevents blood cells called platelets from sticking together & forming blood clots.  The CYP2C19 enzyme converts clopidogrel to its active forms, which is necessary for the drug to function in the body.
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  19 REFERENCES 1. Journal ofthe advanced practitioner in oncology, Anne MC Donnell & Cathygen H Dang https//www.ncbi.nlm.nih.gov/pmc/articles/pmc4093435 Harburoside press. Published in : 2013 July 2) 2. https://www.slideshare.net/mobile/rumanahameed1/drugtransport-and-drug targeting-rumana-hameed. 3. https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2014592/ 4. Cytochrome P450: Genetic Polymorphism and Drug Interactions: F.M. Belpaire & M.G. Bogaert, http://dx.doi.org/10.1080/22953337.1996.11718518 5. Genetic Basis of Drug Metabolism: Margaret K. Ma, Michael H. Woo, Howard L. Mcleod, Am J Health Syst Pharm. 2002;59(21), https://www.medscape.com/viewarticle/444804_5.