farmacogenetica: verso la personalizzazione …...anabolism into cytotoxic nucleotides responsible...
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FARMACOGENETICA:verso la personalizzazione
della terapia
Siena, 28/02/2011
dopo l’infarto del miocardio,i tumori e l’ictus
dopo l’infarto del miocardio,i tumori e l’ictus
Le reazioni avverse ai farmaciLe reazioni avverse ai farmaci
(ADR=ADVERSE DRUGREACTION)
(ADR=ADVERSE DRUGREACTION)
costituiscono la quarta causadi morte negli Usa
costituiscono la quarta causadi morte negli Usa
La maggior parte di questeimprevedibili morti è dovutaa variabilità individuale nelle
risposte ai farmaci
La maggior parte di questeimprevedibili morti è dovutaa variabilità individuale nelle
risposte ai farmaci
L’aspetto speculare di questavariabilità è la mancata efficacia
di un determinato trattamentofarmacologico con esposizione
del paziente ai soli effetti collateralio tossici del trattamento stesso
senza alcun beneficioterapeutico
senza alcun beneficioterapeutico
La variabilità individualenelle risposte ai farmaciha basi genetiche
La variabilità individualenelle risposte ai farmaciha basi genetiche
risiede in differenze di sequenzaesistenti a carico dei genicodificanti per le proteinecoinvolte nella rispostaad un determinato trattamentofarmacologico
risiede in differenze di sequenzaesistenti a carico dei genicodificanti per le proteinecoinvolte nella rispostaad un determinato trattamentofarmacologico
Che cosa è laFarmacogenetica?
La FARMACOGENETICAè la disciplina che studia le
basi genetichedella risposta individuale
ai farmaci
I geni che influenzano la rispostaad un determinato trattamentofarmacologico possono essere
distinti in due grandi classi
I geni che influenzano la rispostaad un determinato trattamentofarmacologico possono essere
distinti in due grandi classi
22
Geni codificanti per il bersaglioterapeutico primario, comeper esempio recettori o enzimi
Geni codificanti per il bersaglioterapeutico primario, comeper esempio recettori o enzimi
Geni codificanti per proteinecoinvolte nell’assorbimento,metabolismo ed escrezionedel farmaco
Geni codificanti per proteinecoinvolte nell’assorbimento,metabolismo ed escrezionedel farmaco
I geni che influenzano la rispostaai farmaci possono presentare
varianti alleliche nella popolazione,cioè, in altri termini, essere
polimorfici
I geni che influenzano la rispostaai farmaci possono presentare
varianti alleliche nella popolazione,cioè, in altri termini, essere
polimorfici
Tali polimorfismi sono spessoa carico di singole basi e vengono
pertanto definiti SNP
Single NucleotidePolymorphisms
Single NucleotidePolymorphisms
Si definiscono polimorficitutti quegli alleli (o loci)
che sono presenti almenonell’1% della popolazione
Si definiscono polimorficitutti quegli alleli (o loci)
che sono presenti almenonell’1% della popolazione
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TRASCRIZIONE
SPLICING
TRADUZIONE
Gli SNPs
vengono classificati
in 3 distinte categorie
SNP delle regioni codificanti(cSNP).SNP delle regioni codificanti(cSNP).
SNP perigenici (pSNP) cheinteressano le regioniregolatorie al 5’, le regionispecificanti i 5’ e 3’ non tradottidel mRNA, gli introni.
SNP perigenici (pSNP) cheinteressano le regioniregolatorie al 5’, le regionispecificanti i 5’ e 3’ non tradottidel mRNA, gli introni.
SNP che si trovano random(rSNP) nelle regioniintergeniche.
cSNPs
POLIMORFISMI A SINGOLONUCLEOTIDE
DELLE REGIONI CODIFICANTI
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pSNPs
POLIMORFISMI A SINGOLONUCLEOTIDE
DELLE REGIONI PERIGENICHE
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X
Si ritiene che in media vi siano 4 cSNPper gene; se si assume che nel genomaumano vi siano 35.000 geni, si stima chevi possano essere tra i 120.000 ei 200.000 cSNP che, con altri appropriaticalcoli, si traducono nel fatto che unindividuo-tipo è eterozigote per circa30.000 aminoacidi
Polymorphism II
2. Insertion/deletion polymorphism: insertion ordeletion of a few nucleotides
3. Variable number tandem repeats: a sequence ofseveral hundred base pairs is repeated (variation inthe number of times)
4. Simple tandem repeats (microsatellites): 2-4nucleotides repeated a variable number of times
Polimorfismi in enzimiresponsabili
del metabolismo dei farmaci
• Nomenclature of CYP genes:– Arabic number for gene family– Capital letter for gene subfamily– Arabic number for individual gene
• CYP enzymes of different gene families have a 40% or morehomology in their amino acid sequences, but enzymes withinone subfamily may have different substrates, regulation, etc.
• Over 70 % of total CYP content of the human liver is shared byseven subfamilies: CYP1A2, CYP2A6, CYP2B6, CYP2C,CYP2D6, CYP2E1, CYP3A
• Extent of metabolism is determined by– Affinity of substrate-enzyme complex– Relative abundance of a given CYP enzyme relative to the
total CYP content
Schema dei principalimeccanismi molecolari
che possono causareun alterato metabolismo
dei farmaci nell’uomo
• In relation to the capability to metabolise a drug thesubjects can be divide in three phenotypes
– Enhanced/extensive metaboliser:• intensive metabolisation, resulting in low plasma
concentration of the drug• usually heteozygote or homozygote dominant
– Intermedier metaboliser– Poor metaboliser or non metaboliser:
• Slow or no metabolisation of the drug resulting in highplasma concentration for an extended time
• Usually homozygote recessive
Effetti dei polimorfismidel citocromo P450
nel trattamentofarmacologico di
“poor metabolizers”
Effetti dei polimorfismidel citocromo P450
nel trattamentofarmacologico di
“poor metabolizers”
PolymorphicenzymePolymorphicenzyme
DecreasedclearanceDecreasedclearance
Adverseeffects
Adverseeffects
Reducedprodrug
activation
Reducedprodrug
activation
CYP2C9CYP2C9 S-WarfarinS-Warfarin BleedingBleeding LosartanLosartan
PhenytoinPhenytoin AtaxiaAtaxia
LosartanLosartan
TolbutamideTolbutamide HypoglycaemiaHypoglycaemia
NSAIDsNSAIDs GI-bleeding(?)GI-bleeding(?)
CYP2C19CYP2C19 OmeprazoleOmeprazole ProguanilProguanil
DiazepamDiazepam SedationSedation
Frequenza di individuiportatori di alleli
con copie multipledel citocromo P450
CYP2D6
Frequenza di individuiportatori di alleli
con copie multipledel citocromo P450
CYP2D6
PolymorphicenzymePolymorphicenzyme
DecreasedclearanceDecreasedclearance
Adverseeffects
Adverseeffects
Reducedprodrug
activation
Reducedprodrug
activation
CYP2D6CYP2D6 TricyclicTricyclic CardiotoxicityCardiotoxicity TramadolTramadol
Antidepres.Antidepres.
HaloperidolHaloperidol
PerphenazinePerphenazine
PerhexilinePerhexiline NeuropathyNeuropathy
SSRIsSSRIs
TolterodineTolterodine
CodeineCodeine
ParkinsonismParkinsonism
NauseaNausea
Ethylmor.Ethylmor.
CYP2D6• Discovered in the 1970s, one of the most widely studied
polymorphisms in drug metabolism• 2% of total liver CYP content• Distribuiton of PM: 7% of Caucasians, 1% of Asians• Involved in metabolism of several drugs
– Psychotropic medications: tricyclic antidepressants, SSRIs,classical and atypical antipsychotics
– Cardiovascular drugs– -receptor antagonists: metoprolol, propranolol, timolol– Phenacetine– D-penicillamine– Codeine– Abused drugs
Distribution of CYP2D6 enzymes indifferent populations
VariantVariantallelesalleles
EnzymeEnzymefunctionfunction
Allele frequency %Allele frequency %
CaucasiansCaucasians AsiansAsians BlackBlackAfricansAfricans
EthiopiansEthiopiansand Saudiand SaudiArabiansArabians
CYP2D6*2xNCYP2D6*2xN IncreasedIncreased 11--55 00--22 22 1010--1616
CYP2D6*4CYP2D6*4 InactiveInactive 1212--2121 11 22 11--44
CYP2D6*5CYP2D6*5 No enzymeNo enzyme 22--77 66 44 11--33
CYP2D6*10CYP2D6*10 UnstableUnstable 11--22 5151 66 33--99
CYP2D6*17CYP2D6*17 ReducedReducedaffinityaffinity 00 NDND 3434 33--99
Ingelman-Sundberg et al., 1999
Struttura degli antimetaboliti usati nellaterapia di alcune forme di leucemia ocome immunosoppressori
TPMT metabolizza tale sostanze: mercaptopurina, azatioprine tioguanidina,ma non si conosce il metabolita fisiologico. Sono antimetaboliti, si intercalanonel DNA e inibiscono la sintesi delle purine
Perchè alcuni soggetti sono sensibili aqueste molecole?
In particolare si riporta che trapiantati ebimbi con leucemie sviluppavano infezionie morivano
Esistono numerose varianti alleliche diTPMT
Determinati soggetti presentano ridotto enzima a causadei polimorfismi che modificano la struttura dell’enzimacon conseguente instabilità e/o degradazionedell’enzima stesso.
E sufficiente diminuire la mercaptopurina nei bimbileucemici se si conosce che sono portatori di un allelepolimorfico.
Il soggetto risponde benissimo senza avere leucopenia.
I soggetti polimorfici per TPMT sviluppano tumoriintracranici: è quindi importantissimo prima di dargli ilfarmaco conoscere il loro profilo farmacogenetico.
Treatment - Polymorphism associations 1
TREATMENT POLYMORPHISM
Fluoropyrimidines DPYD IVS14+1G>ATSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C
Methotrexate ABCC2 C24TTSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C
Irinotecan UGT1A1*28CYP3A4*1BCYP3A5*3ABCB1 C3435T
5-FU: fluoropyrimidine
5-fluorouracil (5-FU) and its derivatives remain some ofthe most commonly prescribed chemotherapy agents.
Approximately 5% of administered 5-FU undergoesanabolism into cytotoxic nucleotides responsible for itsantitumor activity, whereas the other 80%–95% undergoescatabolism into biologically inactive metabolites that areexcreted in the urine and bile.
Dihydropyrimidine dehydrogenase (DPD) catalyzes therate-limiting step in 5-FU catabolism a 5FDHU (5Fluoro-5,6diidrouracile); therefore, variability in this enzyme activityis one of the major factors that influences systemicexposure to fluoro-deoxyuridine monophosphate (FdUMP)and the incidence of adverse effects to 5-FU.
DPYD – Dihydropyrimidine dehydrogenase
Activity: Initial and rate-limiting enzyme in the
catabolism of 5-fluorouracil.
Polymorfism: IVS14+1G>A
The G to A transition in the splice donor site causes the
skipping of exon 14, leading to a truncated protein with
consequent decreased DPYD activity.
Cancer patients, DPYD mutant or heterozygous, with a
complete or nearly complete deficiency of this enzyme
suffered from severe toxicity, including death, following
the administration of 5FU.
TYMS – Thymidylate synthetase
Activity: Important for DNA replication and repair (and
timidina) and primary target for 5-fluorouracil and
capecitabine.
Polymorphism: variable number of tandem repeats
(VNTR) of 28bp (≥ 3 instead of 2) in the promoter region
(TSER).
Homozygous 3R/3R cells overexpress TYMS mRNA
compared with homozygous 2R/2R cells -> possible
chemoresistance.
Low TYMS mRNA expression levels in normal tissue of
patients with the 2R/2R genotype is associated with a
higher risk of cytotoxic effects of 5-FU.
MTHFR – 5,10-methylenetetrahydrofolate reductase(NADPH)
• Activity: It catalyzes the conversion of 5,10-methyleneTHF
in 5-methylTHF. 5,10-methyleneTHF is necessary for DNA
synthesis and maintaining an equilibrate nucleotidic pool.
5-methylTHF is necessary for maintaining the correct DNA
methylation pattern.
• Polymorphisms: 677C>T and 1298A>C: both mutations in
the heterozygous or homozygous state correlate with
reduced enzyme activity and increased thermolability.
MTHFR – 5,10-methylenetetrahydrofolate reductase
(NADPH)
• MTHFR facilitates the formation of the ternary complex 5FU-
TYMS-5,10-methyleneTHF, through which fluoropyrimidines
exert their antineoplastic activity.
• Patients treated with 5-FU, whose MTHFR was mutated, were
significantly at higher risk of toxicity.
Treatment - Polymorphism associations 1
TREATMENT POLYMORPHISM
Fluoropyrimidines DPYD IVS14+1G>ATSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C
Methotrexate ABCC2 C24TTSER (TYMS 28bp VNTR)MTHFR C677TMTHFR A1298C
Irinotecan UGT1A1*28CYP3A4*1BCYP3A5*3ABCB1 C3435T
Irinotecan (Camptosar) is a semisyntheticanalogue of camptothecin and requires metabolicactivation by carboxylesterase to form theactive metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), which in turninhibits topoisomerase-I.
SN-38 is further detoxified via formation of SN-38 glucuronide (SN38G). Irinotecan has potentantitumor activity against a wide range oftumors, and it is one of the most commonlyprescribed chemotherapy agents.Diarrhea and myelosuppression are thedose-limiting toxicities of irinotecan andinterfere with optimal utilization of this importantdrug.
CYP3A4
• CYP3A4 is a monooxygenase that metabolises, throughhydroxylation, tobacco, endogenous steroids and numerousanti-cancer agents.
• The oxidative pathway of irinotecan catalysed by CYP3A4and CYP3A5 result in the formation of inactivemetabolites.
• Polymorphism: -392A>G (allelic variant CYP3A4*1B)• The CYP3A4*1B polymorphism has been associated with
enhanced CYP3A4 expression.• Patients carrying the CYP3A4*1B allele may have
enhanced irinotecan clearance and may beunderexposed.
CYP3A5
Polymorphism: 22893A>G (allelic variant CYP3A5*3)The CYP3A5*3 allele leads to an alternative splicing thatresults in a truncated, inactive protein.Approx. 70% to 90% of Caucasians are homozygousvariant for CYP3A5*3 and thus are deficient in functionallyactive CYP3A5. Patients bearing this mutation have highertoxicity when exposed to the drug.
The wild type allele, CYP3A5*1 is associated totranscript stabilisation and strong increasing of proteinexpression.Patients carrying the CYP3A5*1 allele may have enhancedirinotecan clearance and may be underexposed.
UGT1A1 – UDP glucoronosyltransferase 1A1
• UGT1A1 is involved in glucuronidation of antineoplasticdrugs such as SN38, the active metabolite of irinotecan, aswell as estrogens and their metabolites. UGT1A1 conferspolarity to xenobiotics or endogenous substrates to beeliminated through urine and bile.
• Polymorphism: A(TA)6TAA>A(TA)7TAA (allelic variantUGT1A1*28): the increase in the number of (TA) repeats inthe TATA box region of the UGT1A1 promoter is associatedwith a reduced expression of the gene.
• The reduced glucuronidation rate of SN38, due to thepolymorphism, leads to increase its toxic effect.
(carboxilesterasi)
UGT1A1 TA repeat genotype altersirinotecan neutropenic/activity
35.7
16.3
8.6
0
5
1015
20
25
30
3540
45
50
6/6 6/7 7/7
P=0.007
UGT1A1 genotype
% g
rad
e 4
/5
neu
tro
pen
ia
N=524McLeod H. et al, 2003.
The UGT1A1*28 polymorphism, veryfrequent among Caucasians, has been
reported to be associated with an increasedhematological toxicity (severe neutropenia)in colorectal patients following irinotecan
chemotherapy.
The US FDA has issued recommendations toThe US FDA has issued recommendations toconsider the UGT1A1*28 polymorphismconsider the UGT1A1*28 polymorphism
before startingbefore starting irinotecanirinotecan chemotherapy.chemotherapy.
ABCB1 – ATP-binding cassette, sub-family B(MDR/TAP), member 1 o MDR1 (Multi-DrugResistance) P-glycoprotein
P-glycoprotein is expressed in cells lining the intestine,the biliary tract and the blood-brain barrier and has animportant role in the prevention of absorption and theexcretion of potentially toxic metabolites andxenobiotics.ABCB1 is thought to be one of the most importantproteins involved in irinotecan elimination.
Polymorphism: 1236C>T: the SNP may have anindirect effect such as altering RNA stability.The homozygous T allele of the ABCB1 polymorphismwas associated with significantly increased exposureto irinotecan and its active metabolite SN-38.
Polimorfismi geneticiin bersagli primari di farmaci
ed effetti sulla rispostafarmacologica
Polimorfismi geneticiin bersagli primari di farmaci
ed effetti sulla rispostafarmacologica
Receptor/targetReceptor/target
b2-Adrenergic receptorb2-Adrenergic receptor
MedicationMedication
AlbuterolAlbuterol
5-Lipoxygenase promoter5-Lipoxygenase promoter ABT-761(zileuton)ABT-761(zileuton)
Angiotensin-converting enzyme(ACE)Angiotensin-converting enzyme(ACE)
Enalapril,lisinopril,captopril
Enalapril,lisinopril,captopril
Cholesteryl ester transferproteinCholesteryl ester transferprotein
PravastatinPravastatin
StromelysinStromelysin PravastatinPravastatin
Angiotensin-II T receptorAngiotensin-II T receptor PerindoprilnitrendipinePerindoprilnitrendipine
Receptor/targetReceptor/target
Sulfonylurea receptorSulfonylurea receptor
MedicationMedication
TolbutamideTolbutamide
5-Hydroxytryptamine 2C receptor5-Hydroxytryptamine 2C receptor ClozapineClozapine
Serotonin transporter promoterSerotonin transporter promoter FluvoxamineFluvoxamine
Vitamin D receptorVitamin D receptor 1,25-Dihydroxyvitamin D31,25-Dihydroxyvitamin D3
5-Hydroxytryptamine 2A receptor5-Hydroxytryptamine 2A receptor Clozapineand otherneuroleptics
Clozapineand otherneuroleptics
Dopamine D2 and D3 receptorsDopamine D2 and D3 receptors AntipsychoticsAntipsychotics
Glucocorticoid receptorGlucocorticoid receptor DexamethasoneDexamethasone
Receptor/targetReceptor/target
Nicotinic receptorNicotinic receptor
MedicationMedication
Acetylcholine(-) nicotineAcetylcholine(-) nicotine
Delta opioid receptorDelta opioid receptor HeroinHeroin
Potassium channelsPotassium channels
HERGHERG QuinidineQuinidine
CisaprideCisapride
KvLQT1KvLQT1 Terfenadine,disopyramidemeflaquine
Terfenadine,disopyramidemeflaquine
hHCNE2hHCNE2 ClarithromycinClarithromycin
Receptor/targetReceptor/target
Sodium channelsSodium channels
MedicationMedication
SCN5ASCN5A MexiletineMexiletine
LithiumLithium
Cyclosporin ACyclosporin A
TacrineTacrine
Inositol-p1pInositol-p1p
HLA-DRB1HLA-DRB1
Apolipoprotein E4Apolipoprotein E4
Ryanodine receptorRyanodine receptor Halothane orsuccinylcholineHalothane orsuccinylcholine
ProthrombinProthrombin OralcontraceptivesOralcontraceptives
Peroxisome proliferator-activatedreceptorPeroxisome proliferator-activatedreceptor
InsulinInsulin
1 ARSer or Gly1 AR
Ser or Gly
2 ARArg or Gly2 AR
Arg or Gly
2 ARGlnor Glu
2 ARGlnor Glu
2 ARMet or Val2 AR
Met or Val 2 ARThr or Ile2 AR
Thr or Ile
1 ARGly
or Arg
1 ARGly
or Arg
16164949
2727
3434
164164
389389
Effetti farmacologici delpolimorfismo in posizione 389
del recettore Beta-1
Effetti farmacologici delpolimorfismo in posizione 389
del recettore Beta-1
Effetti farmacologici delpolimorfismi nelle posizioni164, 16 e 27 del recettore
Beta-2
Effetti farmacologici delpolimorfismi nelle posizioni164, 16 e 27 del recettore
Beta-2
La cascata dell’acidoarachidonico
La cascata dell’acidoarachidonico
Associazione farmacogeneticatra il genotipo del promotore
di Alox5 e la rispostaal trattamento anti-asma
Associazione farmacogeneticatra il genotipo del promotore
di Alox5 e la rispostaal trattamento anti-asma
Sp1
Sp1
Sp1
Sp1
Sp1
Sp1
Sp1
Sp1
Sp1
IL PROMOTORE DEL GENE ALOX5
Allele frequenciesAllele frequencies
Allele typeaAllele typea
FrequencyFrequency33
44
55
66
0.0380.038
0.1720.172
0.7720.772
0.0180.018
Gli studi farmacogeneticipossono essere
di tipo
diretto o indiretto
Gli studi farmacogeneticipossono essere
di tipo
diretto o indiretto
Gli studi direttiGli studi diretti
Sono finalizzati all’identificazionedi varianti alleliche nelle regionicodificanti (cSNP) o, regolatorie
(pSNP), di geni prescelti “a priori”sulla base delle conoscenze
a disposizione
Sono finalizzati all’identificazionedi varianti alleliche nelle regionicodificanti (cSNP) o, regolatorie
(pSNP), di geni prescelti “a priori”sulla base delle conoscenze
a disposizione
I polimorfismio
gli aplotipi(combinazione di
polimorfismi)identificati vengono utilizzati
in studi diassociazione allelica
per verificarese essi correlino con un determinato
profilo farmacogenetico
Crossing-over tra cromosomiomologhi durante la meiosi
Crossing-over tra cromosomiomologhi durante la meiosi
Meccanismo di insorgenza di“Linkage disequilibrium”
Meccanismo di insorgenza di“Linkage disequilibrium”
Gli studi indirettiGli studi indiretti
Si avvalgono di SNPs anonimi localizzatisu tutto il genoma, particolarmente nelDNA intergenico, sfruttando la loroassociazione in “Linkage disequilibrium”con i geni responsabili dello specificoprofilo farmacogenetico
Si avvalgono di SNPs anonimi localizzatisu tutto il genoma, particolarmente nelDNA intergenico, sfruttando la loroassociazione in “Linkage disequilibrium”con i geni responsabili dello specificoprofilo farmacogenetico
La Farmacogenetica è un processoche si sviluppa in 3 fasi distinteLa Farmacogenetica è un processoche si sviluppa in 3 fasi distinte
La fase della scoperta ecatalogazione degli SNPs
La fase della scoperta ecatalogazione degli SNPs
La fase della ricerca di correlazionitra la presenza di definiti SNPS(Aplotipi) e determinati profilifarmacogenetici
La fase della ricerca di correlazionitra la presenza di definiti SNPS(Aplotipi) e determinati profilifarmacogenetici
La fase diagnostica La fase diagnostica
Current Methods for genetictesting
• By phenotype: metabolic probe drug or Western blot• By PCR with mutation-specific endonuclease• By PCR and allele-specific hybrization• By oligonucleotide chip hybridization• By laser lithography - guided oligonucleotide chip
hybridization.• By rapid throughput pyrosequencing• Taqman probe screening
Estimated cost to the patient ofGenetic Tests in Clinical Practice
• By simple PCR for one mutation: ~$10• For 50 mutations: ~$150• By Chip for ~ 20 mutations: ~ $70• By Chip for 100 mutations: ~ $250
Clinical PharmacogeneticsSummary
• A good phenotyping probe is critical• Genetic tests need validation just as any other tests• A potent inhibitor can mimic a genetic polymorphism• Not all genetic polymorphisms have a phenotypic
correlate, or clinical effect• The clinical relevance of genetic polymorphisms is
greatest with drugs of narrow therapeutic range, butnot confined to them
• The cost of genetic testing is not likely to be limiting
Pharmacogenetics Websites
• www.pharmgkb.org• The SNP consortium: http://brie2.cshl.org• The Human Genome:
www.ncbi.nlm.nih.gov/genome/guide/H_sapiens.html• CYP alleles: www.imm.ki.se/CYPalleles/• Drug Interactions: www.drug-interactions.com
PHARMACOGENOMICS
• PHARMACOGENOMICS is defined as the study of the interaction of anindividual's genetic makeup and response to a drug.
• The key distinction between pharmacogenetics and pharmacogenomics is that theformer describes the study of variability in drug responses attributed to individualgenes and the latter describes as a study of the entire genome related to drugresponse.
• The expectation is that inherited variation at the DNA level results in functionalvariation in the gene products which will play an essential role in determining thevariability in responses, both therapeutic and adverse, to a drug.
• Automated analysis of genome-wide SNPs allows the possibility of identifyinggenes involved in drug metabolism, transport and receptors, which are likely toplay a role in determining the variability in efficacy, side-effects and toxicity of adrug.
ECOGENETICS
• An extension of pharmacogenetics is the study of genetically determineddifferences in susceptibility to the action of physical, chemicaland infectious agents in the environment.
• This has been referred to as ecogenetics.• Such differences in susceptibility can be either unifactorial or
multifactorial in causation.
Finalità
• Incentivare la ricerca farmacologica sulle basi genetiche dellarisposta individuale ai farmaci
• Farsi promotore di linee guida per un uso etico dellafarmacogenetica
• Promuovere presso gli operatori sanitari la Farmacogeneticaquale strumento per l’ottimizzazione dell’intervento terapeutico
• Stimolare e cooperare con le autorità sanitarie per un uso dellaFarmacogenetica in prospettiva farmacoeconomica
• Integrare le esigenze della Farmacogenetica di base e clinicacon le prospettive ed aspettative dell’industria farmaceutica
• Contribuire alla formazione di esperti nel settore
• Sensibilizzare l’opinione pubblica circa l’uso dellaFarmacogenetica per una medicina personalizzata.
società italiana di farmacologia (SIF)Gruppo di lavoro sulla Farmacogenetica
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