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Metabolism of statins in vitro

Show simple item record 2021-04-07T07:08:09Z 2021-04-07T07:08:09Z 2021-04-07
dc.title Metabolism of statins in vitro en
ethesis.faculty Farmasian tiedekunta fi
ethesis.faculty Faculty of Pharmacy en
ethesis.faculty Farmaceutiska fakulteten sv
ethesis.faculty.URI Helsingin yliopisto fi University of Helsinki en Helsingfors universitet sv
dct.creator Parviainen, Heli
dct.issued 2020
dct.language.ISO639-2 eng
dct.abstract Statins are a commonly used group of drugs that reduce the cholesterol levels in blood and have been shown to reduce cardiovascular morbidity and mortality. However, a considerable percentage of patients experience adverse effects during statin treatment. Statin adverse effects have been associated with genetic polymorphisms and drug-drug interactions that affect the elimination and active transport of these drugs. A more comprehensive knowledge of statin metabolism may be a step towards better management of statin treatments. Statin metabolism both in vivo and in vitro has been subject of study for years. In vitro incubation conditions may considerably affect the observed clearance, and results obtained with different methods or in different laboratories may not be directly comparable to each other. No single in vitro study on a wide panel of statins has previously been conducted. Six statins and some of their metabolites, fourteen compounds in total, were included in the study. The intrinsic clearance (CLint) of these molecules was investigated in vitro on human liver microsomes (HLM) and a panel of eleven cytochrome P450 (CYP) enzymes recombinantly expressed in E. coli. Observed CLint values for each compound in HLM and for each compound-CYP pair with observed depletion were calculated. The percentual contributions of each CYP enzyme to the metabolism of the compounds was calculated. The results obtained with recombinant CYP enzymes (rcCYP) were complemented with studies on HLM with specific chemical inhibitors of CYP enzymes. In this study the metabolism of statin lactones seemed to be faster than the metabolism of the corresponding statin acids. Atorvastatin lactone, 2-hydroxy atorvastatin lactone, 4-hydroxy atorvastatin lactone and simvastatin were extensively metabolized. Atorvastatin, 2-hydroxy atorvastatin, 3R,5S-fluvastatin, 3S,5R-fluvastatin, pitavastatin lactone and simvastatin acid showed intermediate metabolism. 4-hydroxy atorvastatin, pitavastatin, pravastatin and rosuvastatin rates of metabolism were below quantification limit. CYP3A4 had a major role in the metabolism of atorvastatin and its metabolites, simvastatin and simvastatin acid. CYP3A4 also had activity towards pitavastatin lactone. CYP2C9 had a high activity towards both 3R,5S-fluvastatin and 3S,5R-fluvastatin. CYP2D6 may play a part in the metabolism of pitavastatin lactone. CYP2C8 may have some activity towards simvastatin and simvastatin acid. The data is mostly in agreement with previous in vitro and in vivo studies regarding both the metabolism rate of statins and the contributions by different CYP enzymes to the metabolism of statins. Due to the screening nature of the study and some methodological constraints, these data should be considered as preliminary and require confirmation in further studies. en
dct.subject statin en
dct.subject metabolism en
dct.subject drug metabolism en
dct.subject in vitro en
dct.subject cytochrome P450 en
dct.subject CYP en
dct.subject enzymes en
dct.subject human live microsomes en
dct.subject recombinant enzymes en
dct.language en
ethesis.language englanti fi
ethesis.language English en
ethesis.language engelska sv
ethesis.supervisor lib
ethesis.thesistype pro gradu -tutkielmat fi
ethesis.thesistype master's thesis en
ethesis.thesistype pro gradu-avhandlingar sv
dct.identifier.ethesis E-thesisID:f52ecd66-f5b7-45b0-b108-5e32964a7545
personal.identifier lib und lib und
studies.candidatedegree Helsingin yliopisto und
studies.candidatedegree.maturitytestlanguage muu und
ethesis.principalprofessor lib
dct.identifier.urn URN:NBN:fi:hulib-202104071826
dc.type.dcmitype Text
ethesis.facultystudyline Biofarmasia fi
ethesis.facultystudyline Biopharmaceutics en
ethesis.facultystudyline Biofarmaci sv
ethesis.mastersdegreeprogram Lääketutkimuksen, farmaseuttisen tuotekehityksen ja lääkitysturvallisuuden maisteriohjelma fi
ethesis.mastersdegreeprogram Master’s Programme in Pharmaceutical Research, Development and Safety en
ethesis.mastersdegreeprogram Magisterprogrammet i farmaceutisk forskning, utveckling och säkerhet sv

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