| Sažetak | Bolesti krvnih žila vodeći su uzrok pobola i smrtnosti u većini razvijenih zemalja. U Republici Hrvatskoj ateroskleroza, također predstavlja veliki javnozdravstveni problem, te su dijagnoze kao što su akutni infarkt miokarda, ishemijska bolest srca i moždani udar vodeći uzroci smrtnosti. Glavni cilj u borbi protiv bolesti srca i krvnih žila je sprječavanje nastanka aterosklerotičkih nakupina, prevencijom i liječenjem čimbenika rizika. Ukoliko je došlo do nastanka aterosklerotičkih nakupina, cilj je prevencija posljedica ateroskleroze, pretvaranjem nestabilne nakupine u stabilnu, gdje su od velike pomoći lijekovi za smanjenje lipida u krvi. Hiperlipidemija, poremećaj kojeg karakterizira povišena koncentracija lipida u plazmi, utječe
na porast rizika od ateroskleroze. Statini su skupina lijekova koji se koriste prvenstveno za prevenciju i liječenje kardiovaskularnih bolesti. Statini su inhibitori 3-hidroksi-3-metilglutaril-koenzim A-reduktaze, enzima koji je ključan u sintezi kolesterola. Uz svoje dobre farmakološke učinke statini mogu izazvati i različite nuspojave. Učinkovitost lijeka i razvoj nuspojava određeni su različitim čimbenicima kao što su dob i spol bolesnika, funkcija jetre i bubrega, prehrambene
navike, konkomitantne bolesti i lijekovi te farmakogenetička predispozicija. Među najčešćim nuspojavama statina su oštećenja mišićnih i/ili jetrenih stanica. Mišićne nuspojave-miopatije, heterogena su skupina nuspojava koje uključuju pojavu simptoma od blage slabosti i bolnosti mišića bez porasta kreatin-kinaze (CK), do teškog oštećenja mišića sa značajnim porastom CK i potencijalnim ugrožavanjem funkcije bubrega, (rabdomioliza). Miopatije su, uz povećanje jetrenih transaminaza najčešći razlog nepropisivanja statina ili prekida njihove primjene. Pojedini statini se međusobno razlikuju prema mehanizmu biotransformacije, tj. prema metaboličkim enzimima koje koriste, to su prvenstveno citokromi P450(CYP) i transportni proteini iz superporodica ABC i SLC. U studijama je dokazano da u razvoju nuspojava statina bitnu ulogu imaju metabolički i transportni kapacitet pojedinca na kojeg između ostalog utječu genetička predispozicija, te konkomitantne bolesti, lijekovi i
hrana. Rosuvastatin se tek manjim dijelom metabolizira putem CYP2C9 i CYP2C19, stoga ne stupa niti u značajnije interakcije na razni enzima. Značajnu ulogu u prijenosu i eliminaciji rosuvastatina imaju organski anionski transportni polipeptid OATP1B1, kodiran genom SLCO1B1, te ABCG2, čija varijabilnost u ekspresiji i funkciji bitno utječe na varijabilnost
farmakokinetskih parametara, te na učinkovitost odnosno nuspojave rousuvastatina. Istraživanja su pokazala da varijante gena SLCO1B1 521T>C i ABCG2 421C>A mogu poslužiti kao prediktori učinkovitosti i nuspojava rosuvastatina. |
| Sažetak (engleski) | Vascular diseases are the leading cause of morbidity and mortality in most developed countries. In Croatia, atherosclerosis is major public health care problem, and diagnosis such as acute myocardial infarction, ischemic heart disease and stroke, are leading causes of death. The main objective in the battle against heart and vascular diseases is to prevent the occurrence of atherosclerotic lesions, by prevention and treatment of risk factors. If the atherosclerotic lesion formation has occured, the goal is the prevention of the consequences of atherosclerosis, by converting unstable clusters into stable ones, where medications for reducing blood lipids are very helpful. Hyperlipidemia, a disorder characterized by elevated plasma lipids, causes increased risk of atherosclerosis occurence. Statins are a class of drugs which are used primarily for the prevention and treatment of cardiovascular diseases. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the key enzyme in cholesterol synthesis. With its good pharmacological effects,
statins can also cause various side effects. Efficiency of the drug and developing side effects are determined by several factors such as age and sex of patients, liver and kidney function, dietary habits, concomitant diseases and medications, as well as pharmacogenetic predisposition. Among the most common side effects of statins are damaged muscle and /
or liver cells. Muscle side effects - myopathy, are heterogeneous group of side effects that include the appearance of symptoms from mild weakness and muscle pain without an increase in creatine kinase (CK), to severe muscle damage with a significant increase in CK and potential threat on renal function (rhabdomyolysis). Myopathy, along with an increase in hepatic transaminases are most common reasons for non-prescribing of statins or discontinuation of their usage. Some statins differ according to the mechanism of their biotransformation, ie. the metabolic enzymes that are used, primarily the cytochrome P450 (CYP) and transport proteins from the super families of ABC and SLC. Studies have proved that in the development of statine side effects an important role is played by individual’s metabolic and transport capacity which is being affected by genetic predisposition, concomitant diseases, drugs and food. Rosuvastatin is metabolized to a lesser extent by CYP2C9 and CYP2C19, therefore, any significant interaction with enzymes should not be expected. An important role in the transfer and elimination of rosuvastatin have organic anion transporting polypeptide OATP1B1, encoded by the gene SLCO1B1 and ABCG2, whose variability in the expression and function significantly affects the variability of pharmacokinetic parameters, as well as on the effectiveness and side effects of rousuvastatin. Studies have shown that gene variants SLCO1B1 521T> C and ABCG2 421C> A may serve as predictors of efficacy and side effects of rosuvastatin. |
