pattern genetici e farmacoterapia - onda · • giorno 1 - bambino maschio sano nato a termine,...
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Francesco Scaglione, MD, PhD Department of Oncology and Hemato-oncology
Postgradute School of clinical pharmacology
University of Milan
Head of Clinical Pharmacology Unit Niguarda - Hospital
Milan,Italy
Pattern genetici e Farmacoterapia
Differenteefficaciadeifarmaci
Stessa malattia, Stessi sintomi,
Stesso paziente? Different Effects
Stesso farmaco Stessa dose
• Giorno1-bambinomaschiosanonatoatermine,madreassume30mgdicodeina/500mgdiparacetamoloperdolore
• Giorno7-difficoltàl'allaEamentoalsenoeletargia• Giorno11-bambino,stazionariopermaneletargia• Giorno12-pellegrigiastra,allaEamentodifficoltoso• Giorno13-neonatotrovatomorto• concentrazioneema4cadimorfinapostmortem=70ng/mL
(normaleinneona4allaEa4alsenodamadricheassumonocodeina0-2-2ng/mL)
• analisigeno4poCYP2D6–madreconduplicazionegenicaCYP2D6*2x2-metabolizzatoreultra-rapido
• ineona4generalmentehannoridoEacapacitàdimetabolizzareedeliminarelamorfina
Lancet368:704,2006
CASOCLINICO
CODEINA
CYP3A4 CYP2D6
Norcodeina
Mor0ina
Mor2ina-6-glucuronide
Mor2ina-3-glucuronide
effetti
oppioidi
EscrezioneRenale
DuplicazioneCYP2D6nellamadreAltaconcentrazionedimor2ina
Glicurono-coniugazione molto bassa nel neonato
• Pharmacogene+ccontribu+ontopharmacokine+c
parameters.t1/2ofan3pyrineismoreconcordantiniden3calincomparisontofraternaltwinpairs.Barsshowthet1/2ofan3pyrineiniden3cal(monozygo3c)andfraternal(dizygo3c)twinpairs.(RedrawnfromdatainVesellandPage,1968.)
DRUGMETABOLIZINGENZYMES
PhaseI:biotransforma4onreac4ons:oxida4on,hydroxyla4on,reduc4on,hydrolysisPhaseII:conjuga4onreac4ons—toincreasetheirwatersolubilityandelimina4onfromthebody.Thereac4onsareglucuronida4on,sula4on,acetyla4on,glutathioneconjuga4on
TypesofPolymorphisms
• SingleNucleo4dePolymorphism(SNP): GAATTTAAG GAATTCAAG
• Inser4on/Dele4on: GAAATTCCAAG GAAA[]CCAAG
GENETICVARIATION
Pa4entpopula4onwithsamediseasephenotype Pa4entswithnormalresponse
todrugtherapy
Pa4entswithnon-responsetodrugtherapy
Pa4entswithdrugtoxicity
Genotyping
Toxicresponders
Non-responders
Responders
Ipazien3rispondonoinmododifferenteaifarmaci
“One size does not fit all …”
Drug Metabolic Route Alfentanil CYP3A4/CYP3A5 Carisoprodol** CYP2C19 Celecoxib CYP2C9 Codeine** CYP2D6 Cyclobenzaprine CYP1A2, CYP3A4/CYP3A5 Fentanyl CYP3A4/CYP3A5 Hydrocodone** CYP2D6 Hydromorphone UGT2B7
Ibuprofen CYP2C9
**prodrug;
Commonpainmedica4ons Pain Management
Drug Metabolic Route Lidocaine CYP1A2 Methadone CYP2C19, CYP2B6+
Morphine UGT2B7+ (OPRM1)
Naproxen CYP2C9 Oxycodone** CYP2D6, CYP3A4/5 Oxymorphone UGT2B7+ (OPRM1)
Ropivicaine CYP1A2 Tizanidine CYP1A2 Tramadol** CYP2D6 Zolmipitran CYP1A2
LIMITIdellafarmacogene4ca
• Targe4ngcomplessosecoinvolgimentodipiùgeni
• Difficileerichiedetempoperiden4ficarevariazionidigenipocono4
• Interazioneconaltrifarmacieambientedadeterminare
Barrieredellafarmacogene4ca
• Scarsitàdilaboratoridifarmacogene4ca• Scarsaesperienzaneiclinici• Pochifarmacologicliniciconesperienzanell’adaEamentodelladose
Pharmacologic effect
Clinical response
Toxicity Efficacy
DISTRIBUTION
ABSORPTION
ELIMINATION
Pharmacokinetics
Pharmacodynamics
dose administered
drug in tissuesof distribution
concentration insystemic circulation
concentration atsite of action
metabolism and/or excretion
Ø Pharmacokinetic factors
- Absorption - Distribution - Metabolism - Elimination
Ø Pharmacodynamic factors - Target proteins - Downstream messengers
Determinants of Drug Efficacy and Toxicity Apa4ent’sresponsetoadrugmaydependonfactorsthatcanvaryaccordingtotheallelesthatanindividualcarries,including:
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