Farmakogenetika tramadola i individualizacija terapije

master's thesis

• Title (english): The pharmacogenetics of tramadol and therapy individualization
• Author: Karolina Miljak
• Mentor: Karmela Barišić (mentor)
• Committee member: Karmela Barišić (predsjednik povjerenstva)
• Committee member: Vesna Bačić Vrca (član povjerenstva)
• Committee member: Nada Božina (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2019-09-12, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Farmakogenetika je znanstvena disciplina koja proučava utjecaja individualnih razlika u slijedu DNA na učinkovitost i
toksičnost farmakoterapije. Najčešće ispituje varijante gena koji kodiraju enzime uključene u metabolizam i prijenos
lijeka preko različitih membrana. Cilj je rada ukazati na moguću važnost farmakogenetičke analize kao korisnog alata
u svakodnevnoj kliničkoj praksi za optimalnu prilagodbu doziranja lijekova čija primjena može rezultirati razvojem
serotoninskog sindroma. Ovim su radom prikazani enzimi i transporteri ključni za metaboličke puteve tramadola i
čestih konkomitantno primijenjenih antidepresiva. Opisani su mogući patogenetski mehanizmi nastanka
serotoninskog sindroma kao posljedica farmakogenetičke predispozicije te interakcija lijekova. Također su opisani i
geni koji kodiraju enzime CYP2D6, CYP2C19, CYP3A4, UGT2B7 i transportere P-glikoprotein (Pgp/MDR1/ABCB1) i SERT. Na primjerima opisa slučajeva iz kliničke prakse prikazani su mogući mehanizmi interakcija lijek-lijek-gen. Rezultati analiza upućuju na utjecaj farmakogena u moduliranju interakcija konkomitantno primjenjenog tramadola i antidepresiva, u ovom slučaju escitaloprama, venlafaksina i paroksetina, koje su rezultirale razvojem serotoninskog sindroma. U zaključku treba istaknuti da bi provedba genotipizacije relevantnih gena metaboličkih enzima i transportera važnih u farmakokinetici tramadola i antidepresiva mogla značajno pridonijeti individualiziranom pristupu u primjeni navedenih lijekova te minimalizaciji rizika razvoja štetnih učinaka uključujući serotoninski sindrom.
U širem kontekstu ovaj rad ukazuje na potencijal farmakogenetike u personaliziranom pristupu svakom pacijentu radi
postizanja željenih terapijskih ishoda, smanjenja nastanka nuspojava, te poboljšanja opće kvalitete zdravstvene skrbi.

Abstract (english)

Pharmacogenetics is a science discipline that studies impacts of interindividual differences in DNA on
pharmacotherapy efficacy and toxicity. Most frequently examined are gene variants encoding enzymes responsible for
drug metabolism and transmembrane transport. The aim of this paper is to showcase the potential of pharmacogenetic
analysis as an useful tool for timely dosing adjustment of medications, containing a high risk of serotonin syndrome
development, in every day clinical praxis.
This paper takes into account drug metabolizing enzymes and drug transporters of tramadol pathway and
concominantly perscribed antidepressants. Showcased are hypothetical pathogenetic mechanisms of serotonin
syndrome development as a result of pharmacogenetic predisposition and drug interactions. Genes coding for
CYP2D6, CYP2C19, CYP3A4, UGT2B7, MDR1 and SERT are characterized. Clinical case examples were used to
describe potential mechnisms of drug-drug-gene interactions. The results of pharmacogenetic analysis confirmed that
pharmacogenes have an impact on tramadol-antidepressant polytherapy modulation, in this case escitalopram,
vanlafaxine and paroxetine, causing serotonin syndrome development. In conclusion, genotyping genes coding for
important metabolic enzymes and transporters of tramadol-antidepressant pharmacokinetics could significantly
contribute to individual approach in administration of these drugs and minimize risks of adverse effects incidents,
including serotonin syndrome. In a broader context, this paper presents potenitial of pharmacogenetics in personalized
approach to every patient in terms of achieving optimal therapy results, avoiding side effects and improving health
care quality.

• Keywords: farmakogenetika; farmakogenetska analiza; polimorfizmi; tramadol; antidepresivi; serotoninski sindrom; liječenje; personalizirana terapija
• Keywords (english): pharmacogenetics; pharmacogenetic analysis; polymorphisms; tramadol; antidepressants; serotonin syndrome; medical terapy; personalized therapy
• Language: croatian
• URN:NBN: urn:nbn:hr:163:785681
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-02-12 12:25:54