The Impact of Human Genome on Interindividual variability
in
Drug Response
Ms. Dumbare Swamini, Kumavat Nandini, Dr. S. D. Mankar
Dr. S.B. Bhawar Pravara Rural College of Pharmacy, Pravaranagar
*Corresponding Author E-mail: nandinikumavat19@gmail.com
ABSTRACT:
Pharmacogenomics is an important aspects of clinical genomics i.e an increasingly large number of patients it have extremely broad cast application a pharmacogenomics has evolved from early Pharmacogenetic studies of candidate gene often genes. Pharmacogenomics has the potential to mitigate adverse drug reaction and optimise pharmaco therapy in individual it has the potential to revolutionize the practice of medicine and promises to in an area of personised medicine in which drug and drug combination optimised for each Individual unique genetic makeup. It is well recognised that most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications interindividual differences in polymorphism of incoding genes in drug metabolising enzymes drug transporter, Target drugs eg. receptors, enzymes. The ultimate goal is to provide new strategies for optimising drug therapy based on each patient genetic determinants of drug efficacy and toxicity.
KEYWORDS: Pharmacogenetics, polymorphism, drug metabolism, drug therapy.
INTRODUCTION:
Interindividual variation –Pharamacokinetic:
Variation in the drug concentration achieved by equivalent doses is a much more important causes of the interindividual variation in drug response encountered in clinical practice. There are many reason why the absorption, metabolism and excretion of drug might vary.1
Intrinsic and Extrinsic factors also affect in drug absorption of inter individual variation.
The important goal of the field of pharmacogenomics is to utilised genomic information in order to optimise pharmaco therapy for individual. Pharmacogenetics and pharmacogenomics are the major immerging trends in medical sciences.
The development of pharmacogenomics is a natural sequeia to the success of the initial human genome sequencing project.2,3 The human genome project is an international research efforts to determine the DNA sequence of the entire human genome. Human genome has the primary goal of determining the sequence of chemical base pair which make up human DNA and of identifying an mapping the total genes of the human genome.4,5
In recent years, next generation sequencing (NGS) techniques have provided with powerful approaches for CNV detection. Drug response of individual patient is primarily determined by the pharmacokinetic and pharamacodynamic properties of prescribed drug which is directly or indirectly affected by polymorphism in drug metabolising enzyme and transporter. Genomic difference between individual are present approximately every 300 to 1000 nucleotides with over 14 million single nucleotide polymorphism (SNPs) distributed throughout the entire human genome.6,7 The elucidation of the molecule genetic basis for inherited difference in drug metabolism began in the late 1980s, With the initial cloning of a polymorphic human gene incoding the drugs metabolising enzyme debrisoquin hydroxylase (CYP2D6) drug response phenotypes include adverse drug events and therapeutic efficacy. Pharmacogenomics is the branch of science concerned with the identification of genetic attributes of an individual that lead to variable responses to drugs. The most common variation in the human genome are called single nucleotide polymorphism (SNPs).8,9 Pharmacogenetic starts with an unexpected drug response and evaluate its genetic cause, while pharmacogenomics begins with looking for genetic variation within a population that may explain certain observed responses to a therapeutic drug Identification of DNA variants that most significantly contribute to the population variation in each trait is one of the fundamental objectives of genetics10,11. The causative factors for variation in drug response are complex and multifold with direct or indirect consequences among them stabilly inherited genetic factors are the major variable, whereas others include environmental factors like chemical and radiation exposure, lifestyle factors like drinking, smoking and exercise and physiological factors like age, sex, liver and kidney function, pregnancy and starvation different population have varied allele frequencies in genes of both drug metabolising enzymes and transporters precision medicine will help to improve the selection of disease Target and lead to the identification of patient population that exhibit better clinical result at normal doses.12,13
Genomics was established by fred sanger when he first sequence the complete genomes of a. Virus and a mitochondrion the actual term genomics is thought to have been coin by doctor. Tom Roderick, a geneticist at the Jackson laboratory over beer at a meeting held in Maryland on the mapping of the human genome in 1986 the notion that genetic variants might modulate variability in drug action was first proposed by the English physiologist Garrod he suggested that enzymatic defects lead not only to accumulation of endogenous substrates in “inborn errors of metabolism“, but also to accumulation of exogenously administered substrates such as drugs, food stuffs, and toxins with clinical consequences. The term Pharmacogenetic was coined in 1959 and the first textbook was published in 1962.14,15
The existence together of many forms of DNA sequences at a low cost within the population a discontinuous genetic variation that results in different forms or types of individual among the members of a single species allele have a different DNA sequences. polymorphic locus – the frequency of the most common allele is less than 99 percent.16,17
A polymorphism have been reported in both phases of drug metabolising enzyme and affect the pharmacokinetic profile of a drug for a given patient genetics in general is a branch of biology related to survey of genes and genetic variation.18
Polymorphism arise as a result of mutation. An alteration that changes only a single base pair is called point mutation.
The most common form of point mutation is transition, comprising the substitutions of one nucleotide with another and the size harbouring such changes is termed a single nucleotide polymorphism. For drug metabolising enzyme the molecular mechanism of inactivation include splice slight mutations resulting in exon skipping eg. (DPD, CYP2C19), micro satellite nucleotide repeats eg. Genetic polymorphism of drug metabolising enzyme are quite common because these enzyme are not essential for an evolutionary perspective. Allelic variants have also been identified (CYP3A4*2, CYP3A4*3), one of which (CYP3A4*2) has altered catalytic activity for nifedipine but not testosterone. A polymorphism recently discovered in intron 3 of the human CYP3A5 gene creates an ectopic splice slight, leading to a premature codon in the encoded mRNA19. Essentially all polymorphisms studied to date differ in frequency as among ethnic and racial group. Thiopurine S- methyle transferase (TPMT) is a polymorphic phase 2 enzyme that catalyses the S-methyle transferase of Thiopurine medications (mercaptopurine, thioguanine and azathioprine, which is the inactivation pathway in hematopoietic tissue. For the TPMT polymorphism, all patients who inherit to nonfunctional TPMT allele will developdose-limitinghematopoietic toxicity that can be fatal if these patients are treated with full dose of Thiopurinemedications20. The molecule genetic basis of TPMT polymorphism has been clarified and molecular diagnostics are now available to prospectively identify TPMT difficent and heterozygote patient21.
|
gene |
Drug |
Responder of genotype and phenotype |
Nonresponder Genotype or phenotype |
|
TPMT |
Thioguanine, Azathioprine, Mercaptopurine. |
Extensive metaboliser |
Poor metaboliser |
|
CETP |
Pravastatin |
B1 |
B2 |
|
ACE |
Enalapril |
Insertion(I) |
Deletion (D) |
|
5-HTT |
Fluvoxamine |
Long(I) |
Short(S) |
|
CYP2C9 |
Warfarin |
Extensive metaboliser |
Poor metaboliser |
|
CYP2D6 |
Desipramin |
Extensive metaboliser |
Poor metaboliser |
|
HER2 |
Trastuzumab |
HER2neu positive |
HER2neu negative |
Phase 1 enzyme exhibit functional genetic polymorphism such that a subsate of a population inherits a deficiency of the enzyme activity. This deficiency can be increased pharmacologic effect for medications inactived by these enzyme such as tricyclic anti depressant’s and CYP2D6 antipsychotic and CYP2D6. The potential seriousness of these polymorphism is further exemplified by the fatal toxicity that occurred in a CYP2D6 -deficient patient who received full dosages of Fluoxctine despite and inherited deficiency of CYP2D6 the primary inactivation pathway22. One of the most extensively studied genetic polymorphism known to influence Drug metabolism and response in the debrisoquin type CYP2D6 oxidation polymorphism. Quinidine is the most potent inhibitor of CYP2D6. Quinine which is diastereoisomer of quinidine, is several 100 time’s less potent inhibitor than quinidine. However quinidine is not a substrate of CYP2D6.
CYP2C9 that is cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in metabolism by oxidation of both xenobiotic, including drugs and endogenous compound, including fatty acids. In human, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme. CYP2C9 is a crucial cytochrome P450 enzyme, which plays a significant role in metabolism by oxidation. About 100 therapeutic Drugs are metabolised by CYP2C9 including drugs with a narrow therapeutic index such as warfarin and phenytoin, another routinely prescribed drugs such as acenocoumarol, glipizide and some nonsteroidal anti immflamatory drug. CYP2C9 has some weak inhibitors such as Ceritinibe, Diosmin, Disulfiram, Fluvastatin, Fluvoxamine, Voriconazole23
|
Cytochrome P450 |
Phentotype |
Frequency in ethnic groups |
Total drugs # |
Example |
|
CYP2D6 |
Poor |
White6% |
>100 |
Codeine, |
|
metabolism |
AA 2% |
nortriptyline,dextromethorphan |
||
|
|
Asian 1% |
fluoxetine propranolol |
||
|
Ultra rapid |
Ethopian |
|
||
|
|
20%, |
|
||
|
|
Spanish 7%, |
|
||
|
|
Scand 1.5% |
|
||
|
CYP2C9 |
Reduced activity |
|
>60 |
Tolbutamide, diazepan, ibuprofen, Warfarin |
|
CYP2C19 |
Poor metaboliser |
Asian 23% White 4% |
>50 |
Omeprazole, plaquenil. |
|
N-Acetyl transferase |
Poor metaboliser |
White 60% AA 60% Asian 20 % Intuit 5% |
>15 |
Isoniazid,procainamide,hydralazine |
|
Thiopurine methyl transfrase |
Poor metaboliser |
Low in all populations |
<10 |
6-Mercaptopurine |
5-HTT is a gene moderate a person’s likely hood to experience depressions after stressful events. The link between 5-HTT and mood disorders is thought to be related to the protein products as a serotonin transporter. The 5-HTT gene encodes the serotonin transporter protein and is thus active in the serotonin nerve pathway. This pathway is involved in controlling mood, emotions, aggression’s, sleep and anxiety.
Figure No-(3) Functional polymorphism (5-HTTLPR) in the serotonin transporter gene.
As a serotonin transporter, the protein encoded by the 5-HTT gene is responsible for the reuptake of serotonin into the presynaptic cleft to signal the adjuscent neuron23. CYP2C19 i.e cytochrome P450 (CYP2C19 ) is an enzyme involved in the bioactivation of various important therapeutic drug, from pro- drugs to an active inhibitor of platelet action. It include some proton pump inhibitors and anti epileptic drugs. These proteins are monooxygenase that catalyses many reactions involved in the drug metabolism and synthesis of cholesterol, steroids and other lipids. Polymorphism within the genes associated with variable abilities to metabolised drugs24
CETP i.e cholesterol ester transfer protein and high density lipoprotein cholesterol (HDL-C) have casual roles in atherothrombosis. One method to evaluate this issue is to examine whether polymorphism in the CETP gene that impact on HDLC level also impact on the future development of myocardial infraction. CETP promote the transfer of cholesteryl ester form High density lipoprotein cholesterol to other lipoprotein particles and individual genetically difficent for CETP often have extremely high HDLC level. CETP shuttles cholesterol ester form High density lipoprotein particles (HDL) to low density lipoproteins (LDL) high CETP activity lowers the HDL
Total cholesterol ratio potentially increasing risk for coronary artery disease
Angiotensin converting enzyme (ACE) plays an essential role in to physiological system. One leading to production of angiotensin 2nd an the other to the degradation bradykinin. The discovery that ACE levels are under genetic control ushered in a new era of investigation; most studies focused on an insertion/ deletion polymorphism in intron 16 of the ACE gene as a marker for a functional polymorphism. The structure ACE gene May be the result of duplication of Ancestral gene. The DD genotype has been consistently associated with increased ACE activity and ACE I /D genotype have been associated with various clinical effects of ACE inhibitors, including Reno protective effects, blood pressure reduction, left ventricular hypertrophy reduction, and improvements in endothelial function25.
Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic system. More generally, xenobiotic metabolism is a set of metabolic pathway that modify the chemical structure of xenobiotics, which are compound’s foreign to an organisms normal biochemistry, such as any drug or poison. The metabolism of pharmaceutical drugs is an important aspects of pharmacology and medicine. Drug metabolism is divided into 3 phases.
In phase 1, enzyme such as cytochrome P450 oxidase introduced reactive or polar groups into xenobiotic. These modified compounds are then conjugated to Polar compounds in phase 2 reactions. These reaction are catalysed by transferase enzyme such as glutathione S transferase. Finally in phase 3rd, the conjugated xenobiotic may be further processed, before being recognised by efflux transporters and pump out of cell. Drug metabolism often converts lipophilic compounds into hydrophilic products that are more readily excreted.
Inhibition of a drug metabolising enzyme occur via two principle mechanism: Reversible and irreversible (mechanism based inactivation). Clinically either of these mechanisms can lead to reduce clearance of coadministered drug and potentially toxic level may be reached. The cytochrome P450 (CYP) enzyme families 1-3 are responsible for 70-80 percent of all phase 1 dependent drug metabolism. In humans in 90 percent, depending on only 6 CYP’s: CYP1A2, CYP3A4, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. CYP3A4 is of all human CYPs the one of that is metabolising the greatest number of drugs. As may be expected from these fact, the greatest number of metabolic drug -drug interaction where observed with substrates of CYP3A4. Reversible inhibition of CYP3A4 – mediated detoxication of a given drug A caused by 2nd drug B, which is also a substrate of CYP3A4, may lead to fatal accumulation of drug A, the saviarity of the effect depending on the relative contribution of CYP3A4 to the total metabolism of the drug in question,on the affinity of these drugs for CYP3A4 and on their relative quantities used. These serious drug – drug interactions may be avoided by the correct application of knowledge on drug metabolism26,27
Drug metabolism is an drug clearing event for systemic circulation influencing efficacy and toxicity in humans and preclinical species. Membrane drug transporter plays an important role in the uptake, distribution and elimination of both endogenous substance and drugs in the body because they help regulate the flux of many substances across cell membranes.28,29 They are often complicated in detoxification mechanism, multi-drug resistance and clinical DDIs. There is an upper limit for the rate of drug metabolism in the vast majority of the drugs. These is due to the saturation of the enzyme needed for the metabolic pathway to takes place. However, the therapeutic dosage usually used for significantly below the level of saturation and, as a result, the metabolism rate increases with the concentration of the drug. This is referred to as first order kinetics.30 In first order kinetics, the metabolism rate is a constant fraction of the concentration of the drug in the body. In some cases, therapeutic dosage of the drug can lead to the saturation of the enzyme sites. In such cases, the metabolism remains constant despite increase’s in the dosages of the drug. These is referred as zero order kinetics31,32
Drug therapy is an ongoing process in which Pharmacist actively review record, and identify drug therapy problems such as adverse drug events In (ADEs) and Communicate with prescriber’s when problem occur. Drugs are a dualistic therapeutic tool.33 Drug can be defined as any substance or product that is used to modify or explore physiological system or pathological States for the benefit of the recipient.34 Every health care practitioner is responsible for helping patients with problems that requires certain level of professional complexity to identify, prevent or resolve. A drug therapy problem is an any undesirable event experienced by a patient which involves, or is suspected to involve, drug therapy and that interferes with the desired goal of therapy35 The improper use of drugs can lead to patient morbidity and even mortality36,37
Drug/dose selection:
The cause of drug related problems related to the selection of the drug or dosage schedule, inappropriate drug selection, inappropriate dosage selection, more cost effective drug available.38
Risk factor for drug therapy problems:
Although medications provide a benificial effect in most patients, the elderly are at particular risk for drug related problems, which have been defined as undesirable patients experiences related to drug therapy that actually or potentially interfere with desired patients outcomes39
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Received on 23.08.2023 Modified on 19.10.2023
Accepted on 04.11.2023 ©A&V Publications All right reserved
Res. J. Pharmacology and Pharmacodynamics.2024;16(1):19-24.
DOI: 10.52711/2321-5836.2024.00004