Utjecaj farmakogenetičkih varijacija metaboličkih enzima i transportnih proteina na nastanak nuspojava inhibitora 3-hidroksi-3-metil-glutaril koenzim A (HMG-CoA) reduktaze

Mirošević Skvrce, Nikica (2014) Utjecaj farmakogenetičkih varijacija metaboličkih enzima i transportnih proteina na nastanak nuspojava inhibitora 3-hidroksi-3-metil-glutaril koenzim A (HMG-CoA) reduktaze. PhD thesis, Sveučilište u Zagrebu.

Preview

PDF Download (1MB) | Preview

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are widely used for the treatment of hypercholesterolemia. Their efficacy in preventing cardiovascular events has been shown by a large number of clinical trials. However, adverse drug reactions (ADRs), sometimes serious, including myopathy or rhabdomyolysis, are associated with the use of statins. Newly identified risk factors for statin induced toxicity are genetic variants of drug metabolizing enzymes and membrane transporters. The aim of our study was to show influence of ABCB1, ABCC2, ABCG2, SLCO1B1 and CYP2C9 gene variants on development of atorvastatin, simvastatin and fluvastatin induced, dose related ADRs. One hundred sixty two patients that experienced statin induced ADRs and 162 controls matched for age, gender, dose and cyclosporine use were enrolled in the study. We found that ABCG2 421C>A and CYP2C9*3 variants were associated with fluvastatin induced ADRs, ABCG2 421C>A and SLCO1B1 521 C>A variants were associated with simvastatin and atorvastatin ADRs. Our study first linked statin ADRs and ABCG2 variants. Also, our study first showed importance of pharmacogenetic predisposition for developing fluvastatin ADRs.

Abstract in Croatian

Inhibitori 3-hidroksi-3-metil-glutaril-koenzim-A (HMG-CoA) reduktaze (statini) najpropisivaniji su lijekovi u liječenju hiperkolesterolemije. U velikom broju kliničkih ispitivanja dokazana je njihova učinkovitost u smanjivanju rizika nastanka kardiovaskularnog događaja. Međutim, statini mogu imati i ozbiljne nuspojave kao što su miopatija i rabdomioliza. Novi identificirani rizični faktori za nastanak toksičnosti statina su genetičke varijante metaboličkih enzima i prijenosnika. Glavni cilj rada bio je odrediti učinak genskih varijanti CYP2C9, ABCB1, ABCC2, ABCG2 i SLCO1B1 na nastanak nuspojava povezanih s primijenjenom dozom simvastatina, atorvastatina i fluvastatina. U studiju je bilo uključeno 162 bolesnika koji su iskusili nuspojave povezane s dozom atorvastatina, fluvastatina i simvastatina te 162 bolesnika koji su uzimali ispitivane statine i nisu iskusili nuspojave (kontrolna skupina). Kontrolna skupina ispitanika je prema godinama, spolu, dozi i primjeni ciklosporina odgovarala bolesnicima koji su razvili nuspojavu. Rezultati studije pokazuju kako su varijante gena ABCG2 421C>A i CYP2C9*3 povezane s nastankom nuspojava fluvastatina, a varijante gena ABCG2 421C>A i SLCO1B1 521 C>A s nuspojavama atorvastina i simvastatina. Naša studija je prva povezala varijante gena ABCG2 s nastankom nuspojava statina. Naša je studija također prva ispitala i pokazala važnost farmakogenetičke predispozicije za nastanak nuspojava fluvastatina.

Actions (login required)

View Item

Downloads