| Abstract | CYP2D6 je najopsežnije istražen polimorfni enzim koji sudjeluje u metabolizmu lijekova. Gen CYP2D6 je visoko
polimorfan te je do danas otkriveno barem 112 alelnih varijanti koje kodiraju za inaktivni enzim, enzim sa
smanjenom, normalnom ili povećanom enzimskom aktivnosti. Ovisno o kombinaciji alela i sposobnosti metabolizma
lijekova, razlikujemo četiri metabolička fenotipa. Fenotip brzog metabolizma (EM) se smatra normalnom
karakteristikom najvećeg dijela populacije, a javlja se u osoba s dva potpuno aktivna alela. Pojedinci s deficitom
enzima (5 – 10 % pripadnika bijele rase) klasificiraju se kao spori metabolizatori (PM). Karakterizira ih nedostatak
aktivnog alela te posljedično smanjena aktivnost enzima kodiranog tim alelom što rezultira nakupljanjem lijeka u
organizmu i povećanim rizikom od pojave neželjenih učinaka lijeka. Među ostalima je enzimska aktivnost veoma
varijabilna te se kreće od ekstremno visoke u vrlo brzih metabolizatora do smanjene u srednjih (intermedijarnih)
metabolizatora. Osim značajne interindividualne varijbilnost, zabilježena je i značajna međuetnička varijabilnost u
raspodjeli alelnih varijanti CYP2D6 koja podrazumijeva i postojanje "populacijski specifičnih" alelnih varijanti.
Usprkos niskoj zastupljenosti enzima CYP2D6 (2 – 4 %) u odnosu na druge jetrene enzime CYP, ovaj enzim
sudjeluje u biotransformaciji otprilike 20 – 25 % lijekova dostupnih na tržištu. Enzim CYP2D6 sudjeluje u
metabolizmu velikog broja klinički značajnih lijekova, uključujući opioide (kodein, tramadol), antidepresive
(amitriptilin, imipramin, fluoksetin, mianserin, venlafaksin), antipsihotike (aripiprazol, haloperidol, olanzapin,
risperidon), antitustike (dekstrometorfan), β-blokatore (metoprolol, bufuralol, propranolol), protutumorske lijekove
(tamoksifen) i antiemetike (ondansetron i tropisetron). Genotipizacija CYP2D6 je jedan od alata koji se koriste
prilikom provođenja personaliziranog liječenja, što rezultira povećanjem djelotvornosti terapije i smanjenjem troškova
liječenja. Procjenjuje se da bi takav personalizirani pristup liječenju na temelju genetskih značajki mogao biti
relevantan za terapiju s 10 – 20 % lijekova. U ovom radu se razmatra utjecaj genetske varijabilnosti CYP2D6 na
klinički ishod i terapijski učinak lijekova-supstrata CYP2D6. |
| Abstract (english) | CYP2D6 is the most extensively studied polymorphic drug-metabolizing enzyme. CYP2D6 gene is highly
polymorphic with at least 112 allelic variants discovered so far which encode an inactive enzyme, enzyme with
reduced, normal or increased enzyme activity. Subjects are classified into four metbolic phenotype groups, depending
on combination of alleles and the ability to metabolise xenobiotics. Extensive metabolism (EM) is considered to be a
characteristic of the normal population and is found in subjects with two fully functional alleles. Individuals who are
poor metabolisers have no active alleles and, therefore, lack functional enzyme activity which, consequently, results
in accumulation of specific drug substrates and adverse drug reaction (ADR) occurrence. Among other subjects,
enzyme activity is highly variable and ranges from extremely high in ultrarapid metabolizers to reduced in
intermediate metabolizers. Apart from significant interindividual variability, a significant interethnic variability in
distribution of CYP2D6 allelic variants has also been described, including existence of ‘population-specific’ allelic
variants.
Although CYP2D6 constitutes only 2 – 4 % of the total hepatic CYPs, it is one of the most important drug
metabolizing enzymes due to its role in biotransformation of approximately 25 % of clinically used drugs. CYP2D6
enzyme is involved in the metabolism of numerous clinically significant drugs including opioids (codeine, tramadol),
antidepressants (amitriptyline, imipramine, fluoxetine, mianserin, venlafaxine), antipsychotics (aripiprazole,
haloperidol, olanzapine, risperidone), antitussives (dextromethorphan), beta-blockers (metoprolol, bufuralol,
propranolol), anticancer drugs (tamoxifen) and antiemetic drugs (ondansetron i tropisetron). Genotyping of CYP2D6
is one of the tools used for implementation of personalized drug treatment which results in increased drug efficacy
and decreased cost of ADR treatment. It is estimated that such personalized gene-based treatment could be relevant for
10 – 20 % of all drug therapy. In this thesis, the impact of the CYP2D6 genetic variability on the clinical outcome and
therapeutic and/or adverse effects of drug-substrates of CYP2D6 is reviewed. |
