| Abstract | Prema podatcima WHO-a, koronarna arterijska bolest (CAD) postala je jednom od najvećih „ubojica“ suvremenog
svijeta. Dislipidemija, odnosno povišene razine ukupnog kolesterola, lipoproteina niske gustoće (LDL), triglicerida (TG) ili
snižene razine lipoproteina visoke gustoće (HDL), smatra se jednim od kritičnih čimbenika za razvoj CAD-a. U posljednje
su vrijeme statini najšire propisivani lijekovi u prevenciji i terapiji CAD-a i ishemijskog inzulta. Štoviše, oni dokazano
smanjuju morbiditet i mortalitet snižavanjem razine LDL - kolesterola u krvnoj plazmi. Međutim, statini uzrokuju mnoge
ozbiljne nuspojave, poput miopatije i rabdomiolize. Štoviše, kako se statini koriste u dugotrajnoj terapiji kroničnih bolesti,
velik je i rizik od nuspojava kao posljedice interakcija s drugim lijekovima u politerapiji. Također, utvrđene su velike
interindividualne razlike u smanjenju razina LDL - kolesterola te u incidenciji ADR-a prilikom terapije statinima.
Postoje čvrsti znanstveni dokazi o važnosti membranskih prijenosnika OATP1B1 i BCRP u farmakokinetici statina.
Oba transportera pokazuju značajnu genetičku varijabilnost, a učestalost polimorfizama SLCO1B1 521T>C i ABCG2
421C>A ima veliku i populacijsku i rasnu varijabilnost. Varijantni je alel SLCO1B1 521C najučestaliji u europskoj (16 %),
azijatskoj (12 %) i afričkoj populaciji (1 %). Varijantni alel ABCG2 421A je najučestaliji u Azijata (30 %), zatim u bjelačkoj
populaciji (10-15 %), dok je najrjeđi u afričkoj populaciji (2 %). Rezultati ustanovljeni u populaciji Hrvatske u skladu su s
rezultatima dobivenima za druge europske, bjelačke populacije. Polimorfizmi gena povezuju se s varijabilnom kinetikom, ali
i podložnosti razvoja neželjenih učinaka lijekova supstrata, jer varijabilna aktivnost u prijenosu lijekova preko barijera u
probavnom sustavu, na barijeri jetra-žuč te tubulima bubrega u slučaju BCRP, te unos lijeka u jetra putem OATP1B1 mogu
značajno modulirati apsorpciju, distribuciju i izlučivanje lijekova-supstrata. Stoga analiza polimorfizama SLCO1B1 i
ABCG2 može poslužiti u individualizaciji i optimizaciji liječenja statinima te minimalizaciji rizika razvoja nuspojava,
prvenstveno miotoksičnosti i hepatotoksičnosti. |
| Abstract (english) | According to the WHO, coronary artery disease (CAD) has become one of the greatest „killers“ of the modern
world. Dyslipidemia, or elevated levels of total cholesterol, low-density lipoprotein (LDL), triglycerides (TG), or decreased
levels of high density lipoprotein (HDL), is considered one of the critical factors for the development of CAD. Recently,
statins have been the most widely prescribed drugs in the prevention and treatment of CAD and of ischemic stroke.
Moreover, it is proved that they reduce morbidity and mortality by lowering LDL cholesterol levels in the blood plasma. On
the other side, statins may cause many serious side effects, such as myopathy and rabdomyolysis. Moreover, as statins are used in the long-term therapy of chronic diseases, there is a high risk of side effects as a consequence of interactions with other drugs in polytherapy. Also, great interindividual differences were found in the reduction of LDL-cholesterol levels and in the incidence of ADR during statin therapy.
There is a strong scientific evidence of the importance of OATP1B1 and BCRP membrane transporters in statin
pharmacokinetics. Both transporters show significant genetic variability, and the frequency of polymorphisms SLCO1B1
521T>C and ABCG2 421C>A has great both population and racial variability. The variant allele SLCO1B1 521C is most
common in the European (16 %), Asian (12 %) and African (1 %) population, while the ABCG2 421A variant allele is most
common in Asians (30 %), followed by the white population (10 – 15 %), while it is the rarest in the African population (2
%). The results established in this study are accordant to the results obtained for other European, white populations. Gene
polymorphisms are associated with variable kinetics, but also the susceptibility to the development of adverse drug reactions
of the substrate, because variable activity in drug transport across barriers in the digestive system, liver-bile barrier, renal
tubules in case of BCRP, and drug intake in the liver via OATP1B1 can significantly modulate the absorption, distribution
and excretion of substrate drugs. Therefore, the analysis of SLCO1B1 and ABCG2 polymorphisms can serve to individualize
and optimize statin treatment and minimize the risk of side effects, primarily myotoxicity and hepatotoxicity. |
