| Abstract | Cilj istraživanja
Cilj ovoga specijalističkoga rada je prikupiti, kroz pretraživanje znanstvene i stručne literature, i kritički procijeniti relevantne podatke koji se odnose na utjecaj genskih varijanti onih gena čiji proteinski produkti utječu na učinkovitost terapije statinima.
Materijali i metode
Tijekom izrade i pisanja ovoga specijalističkoga rada sustavno je pretražena znanstvena i stručna literature iz područja farmakogenetike, farmakogenomike, farmakoterapije i kardiologije, kako domaća tako i strana. Kao literaturni izvori korišteni su i odgovarajući priručnici, knjige i udžbenici koji se kao nastavna literatura koriste na studijima medicine i farmacije. Za detaljniji opis pojedinih lijekova iz skupine inhibitora hidroksi-metil-glutaril-koenzim-A-reduktaze korišteni su podaci iz Sažetka opisa svojstava lijeka te baze interakcija Lexicomp i Drugs.com. Od dostupnih baza podataka pretraživane su baze podataka Medline i PubMed za ključne riječi: inhibitori hidroksi-metil-glutaril-koenzim-A-reduktaze, statini, farmakogenetika, farmakogenomika, genski polimorfizam.
Zaključak
Do danas je identificirano više gena čiji proteinski produkti imaju utjecaja na farmakokinetiku i farmakodinamiku statina. Za kliničku praksu najznačajnije su varijante (polimorfizmi) onih gena koji kodiraju proteine uključene u farmakokinetiku statina tj. apsorpciju, distribuciju, metabolizam i izlučivanje, a to su enzimi iz porodice CYP-a, P-glikoprotein i organski anionski transportni polipeptid (OATP). Lovastatin, atorvastatin i simvastatin se najviše metaboliziraju putem CYP3A4 i CYP3A5, a fluvastatin putem CYP2C9 i CYP2C8. Metabolizam ovih lijekova može biti djelomično posredovan i putem CYP2D6 ili nekoliko glukuronozil-transferaza (UGT1A1, UGT1A3, UGT2B7). Pravastatin i rosuvastatin imaju minimalnu interakciju s metaboličkim enzimima i uglavnom se izlučuju nepromijenjeni. Zbog toga se smatra da su pravastatin i rosuvastatin najmanje pod utjecajem
genskih varijacija metaboličkih enzima. Kod pacijenata koji su na politerapiji značajno se povećava vjerojatnost neželjenih interakcija lijekova, posebice u slučajevima onih pacijenata koji su zbog genskih polimorfizama spori ili vrlo brzi metabolizatori. Ako se kod takvih pacijenata istovremeno sa statinima primjenjuju i lijekovi koji su inhibitori ili induktori enzima iz obitelji CYP-a, mogućnost nuspojava i toksičnosti značajno raste. Polimorfizam 3435T na MDR1 ili ABCB1 genu povezan je sa smanjenom ekspresijom P-glikoproteina. Inhibicija i indukcija P-glikoproteina je novije otkriven mehanizam koji utječe na interakcije lijekova. Osobe koje su nositelji T/C ili C/C genotipa kod polimorfizma gena SLCO1B1 (rs4149056 (521T>C)) imaju lošiji odgovor na terapiju statinima te imaju veći rizik za razvoj nuspojava za razliku od osoba koji su nositelji T/T genotipa. Genski polimorfizmi koji imaju utjecaj na farmakodinamiku statina od manjeg su kliničkog značaja. Poznavanje genskih polimorfizama ne može apsolutno prognozirati kako će pacijent reagirati na propisanu terapiju, ali može biti dobar putokaz za opreznije doziranje pojedinih lijekova i učestalije praćenje rizičnih pacijenta. |
| Abstract (english) | Objectives
The aim of this work is to search the literature and collect a large number of data for assesment of the impact of gene polymorphisms of the genes whose protein products influence the effectiveness of statin therapy.
Materials and Methods
During the writing and preparation of this thesis, literature by Croatian and foreign authors in the fields of pharmacogenetics, pharmacogenomics, pharmacotherapy and cardiology was systematically reviewed. Manuals, books and textbooks, which are used in studies of pharmacy and medicine were also used. For a more detailed description of certain drugs from the group of inhibitors of hydroxy-methyl-glutaryl-coenzyme-A-reductase, data from the SPC, and base interaction Lexicomp and Drugs.com were used. From available databases, the databases Medline and PubMed were searched for the following keywords: hydroxy-methyl-glutaryl-coenzyme-A-reductase inhibitors, statins, pharmacogenetics, pharmacogenomics, gene polymorphism.
Conclusion
Several genes whose protein products may affect pharmacokinetics and pharmacodynamics of statins have beeen identified so far. In clinical practice, it is the variants (polymorphisms) of genes that encode proteins involved in the pharmacokinetics of statins , i.e. , absorption, distribution, metabolism and excretion, that are the most important. They are enzymes of the CYP family, P-glycoprotein and organic anion transporting polypeptide (OATP). Lovastatin, atorvastatin and simvastatin are mostly metabolised by cytochrome CYP3A4 and CYP3A5, and fluvastatin through CYP2C9 and CYP2C8. The metabolism of these drugs may be partially mediated through the CYP2D6 or several glucuronosyltransferase (UGT1A1, UGT1A3, UGT2B7). Pravastatin and rosuvastatin have minimal interaction with metabolic enzymes and are mainly excreted unchanged. Therefore, it is considered that pravastatin and rosuvastatin are least affected by genetic variations of metabolic enzymes. In patients with polytherapy the possibility of drug interactions increases significantly, especially in the case of patients who are, due to genetic polymorphism, slow or very fast metabolizers. If inhibitors or inducers of CYP enzymes are coadministrated with statins, the possibility of side effects and toxicity increases significantly. 3435T polymorphism of the MDR1 (ABCB1) gene is associated with reduced expression of P-glycoprotein. Inhibition and induction of P-glycoprotein is a recently discovered mechanism that may affect drug interactions. People who are carriers of the T/C or C/C genotype of SLCO1B1 gene polymophysm (rs4149056 (521T>C)) have a poorer response to therapy with statins, and are at greater risk of developing side effects than carriers of the T/T genotype. Genetic polymorphisms that have an impact on pharmacodinamics of statins are clinically less significant. Knowledge of the genetic polymorphisms can not absolutely predict how a patient will respond to prescribed therapy, but can be a good indicator of the need for cautious dosage of certain drugs and frequent monitoring of patients at risk. |
