Influence of artichoke leaf extract on atorvastatin metabolism and optimization of liquid chromatography methods for determination of atorvastatin and metabolites in biological material

[M. A. Crevar Sakač]

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Farmacija - Farmaceutska-medicinska hemija i strukturna analiza /Pharmacy - Pharmaceutical-medicinal chemistry and structural analysis

Atorvastatin pripada grupi antihiperlipidemijskih lekova poznatih pod nazivom statini. Osnovni mehanizam delovanja ovih lekova je specifična, kompetitivna i reverzibilna inhibicija HMG-CoA reduktaze, enzima koji je značajan za proces biosinteze holesterola. Osim direktnog dejstva na biosintezu holesterola, atorvastatin pokazuje niz plejotropnih efekata koji imaju povoljno dejstvo na aterosklerotske promene. Atorvastatin metaboliše u jetri pod dejstvom CYP3A4 enzima pri čemu nastaju dva aktivna metabolita: ortohidroksiatorvastatin i para-hidroksiatorvastatin i tri neaktivna metabolita: atorvastatin-lakton, orto-hidroksiatorvastatin-lakton i para-hidroksiatorvastatin-lakton. Artičoka (Cynara scolymus L., Asteraceae) je zeljasta, jednogodišnja biljka rasprostranjena širom Mediterana. Terapija hiperlipidemija, pored lekova uključuje i nefarmakološke mere (promena ishrane, fizičke vežbe, prestanak pušenja i unošenja alkohola, primena biljnih ekstrakata). Obzirom da su svi delovi artičoke bogati jedinjenjima koja se ponašaju kao prirodni antioksidansi, ekstrakt lista artičoke i atorvastatin se često u terapiji primenjuju zajedno. Cilj doktorske disertacije je da se ispita uticaj vodeno-etanolnog ekstrakta lista artičoke (Tinctura Cynarae) na metabolizam atorvastatina i opravdanost istovremene primene atorvastatina i navedenog biljnog ekstrakta. Za ispitivanja su korišćene komercijalne biljne kapi na bazi artičoke u kojima je kvantifikovan sadržaj cinarina i hlorogenske kiseline primenom HPLC metode (određen sadržaj obe komponente je 0,2 %). Eksperimentalni rad je zasnovan na određivanju i praćenju promene koncentracije metabolita atorvastatina: orto-hidroksiatorvastatina, para-hidroksiatorvastatina i atorvastatinlaktona u uzorcima plazme eksperimentalnih životinja koje su bile na aterogenoj ishrani i koje su primale atorvastatin kao monoterapiju ili zajedno sa ekstraktom lista artičoke. Za izvođenje eksperimenta korišćeni su pacovi soja Wistar. Životinje su podeljene u 5 grupa koje su bile na različitoj ishrani i/ili terapiji. Jedna grupa životinja je tokom celog eksperimenta bila na normalnoj ishrani, dok su preostale četiri grupe do kraja eksperimenta bile na aterogenoj ishrani. U skladu sa prethodno postavljenim planom eksperimenta, različite grupe životinja na aterogenoj ishrani su, posle određenog vremena, primale atorvastatin, ili atorvastatin i ekstrakt lista artičoke, ili samo ekstrakt lista artičoke...

Atorvastatin belongs to the group of antihyperlipidemic drugs known as statins. The basic mechanism of action of these drugs is specific, competitive and reversible inhibition of HMG-CoA reductase, an enzyme involved in cholesterol biosynthesis. In addition, atorvastatin shows many beneficial pleiotropic effects. Atorvastatin is metabolized in the liver under the influence of the CYP3A4 enzyme to two active metabolites: orthohydroxyatorvastatin and para-hydroxyatorvastatin and three inactive metabolites: orthohydroxyatorvastatin lactone, para-hydroxyatorvastatin lactone and atorvastatin lactone. Artichoke (Cynara scolymus L., Asteraceae) is annual plant, distributed throughout Mediterranean. The treatment of hyperlipidemia, in addition to pharmacotherapy, includes nonpharmacological measures (diet changes, physical activity, cessation of smoking and alcohol intake, use of herbal extracts). Since all the parts of artichoke plant are rich in natural antioxidants, artichoke leaf extract and atorvastatin are often used together. The Ph. D. disertation is focused to investigate the effect of aqueous-ethanolic extract of artichoke (Tinctura Cynarae) on the metabolism of atorvastatin and justification of coadministration of atorvastatin and herbal extract mentioned above. Experiments were conducted using commercial artichoke preparation. The contents of chlorogenic acid and cynarin in Tinctura Cynarae were quantified by means of the HPLC method (determined content of both components is 0.2 %). Experimental work is based on determination and monitoring changes in the concentration of atorvastatin metabolites: ortho-hydroxyatorvastatin, parahydroxyatorvastatin and atorvastatin lactone in the plasma samples of experimental animals fed with atherogenic diet and treated with atorvastatin (alone or in combination with artichoke leaf extract). Experiments were conducted on experimental animals (Wistar rats). The animals were divided into 5 groups on different diet and/or therapy. One group of animals was on normal diet all the time during experiment, and the remaining four groups were on the atherogenic diet. Three of these four groups were treated with: atorvastatin, artichoke leaf extract and the combination of atorvastatin and artichoke leaf extract...

ateroskleroza, atorvastatin, ekstrakt lista artičoke, Cynara scolymus L., eksperimentalni dizajn, metabolizam, LC-MS/MS

atherosclerosis, atorvastatin, artichoke leaf extract, Cynara scolymus L., experimental design, metabolism, LC-MS/MS

543.544:615.272.015.4(043.3) 615.451.1:615.272.015.4(043.3)

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