Quercetin És Chrysin Konjugátumok Farmakokinetikai Kölcsönhatásainak in Vitro Vizsgálata

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Quercetin És Chrysin Konjugátumok Farmakokinetikai Kölcsönhatásainak in Vitro Vizsgálata Quercetin és chrysin konjugátumok farmakokinetikai kölcsönhatásainak in vitro vizsgálata Doktori (PhD) - értekezés Dr. Mohos Violetta Karolin Gyógyszertudományok Doktori Iskola A gyógyszerterápia optimalizálásának lehetőségei Program Doktori iskola vezető: Prof. Dr. Pintér Erika Programvezető: Prof. Dr. Botz Lajos Témavezető: Dr. Poór Miklós Pécsi Tudományegyetem Gyógyszerésztudományi Kar Gyógyszerhatástani Tanszék OGYDHT Pécs, 2021. Tartalomjegyzék Rövidítések jegyzéke ................................................................................................................... 3 I. Bevezetés ................................................................................................................................... 5 II. Irodalmi áttekintés ................................................................................................................. 6 II.1. Humán szérum albumin ................................................................................................. 6 II.2. Citokróm P450 enzimek ................................................................................................. 9 II.3. Xantin-oxidáz enzim ..................................................................................................... 15 II.4. Flavonoidok ................................................................................................................... 19 II.4.1. A flavonoidok általános jellemzése ....................................................................... 19 II.4.2. A flavonoidok farmakokinetikája ......................................................................... 22 II.4.3. A chrysin és a quercetin ......................................................................................... 24 II.4.4. A chrysin és quercetin farmakokinetikai interakciói.......................................... 27 III. Célkitűzések ........................................................................................................................ 30 IV. Anyagok és módszerek ....................................................................................................... 31 IV.1. Reagensek ..................................................................................................................... 31 IV.2. Spektroszkópiai mérések............................................................................................. 31 IV.3. Ultraszűrés ................................................................................................................... 33 IV.4. Xantin-oxidáz esszék ................................................................................................... 33 IV.4.1. Xantin-oxidáz esszé 6-mercaptopurin szubsztráttal .......................................... 33 IV.4.2. Xantin-oxidáz esszé xantin szubsztráttal ............................................................ 34 IV.4.3. Xantin-oxidáz esszé hipoxantin szubsztráttal .................................................... 35 IV.5. Citokróm P450 esszék.................................................................................................. 35 IV.5.1. CYP2C9 esszé ........................................................................................................ 36 IV.5.2. CYP2C19 esszé ...................................................................................................... 36 IV.5.3. CYP2D6 esszé ........................................................................................................ 36 IV.5.4. CYP3A4 esszé ........................................................................................................ 37 IV.6. HPLC analízis .............................................................................................................. 37 IV.7. Statisztikai értékelés és IC50 értékek meghatározása ............................................... 39 V. Eredmények .......................................................................................................................... 40 V.1. Chrysin és konjugátumainak kölcsönhatásai szérum albuminnal ........................... 40 V.2. A chrysin és quercetin konjugátumok kölcsönhatásai CYP enzimekkel ................. 44 V.2.1. A chrysin konjugátumok kölcsönhatásai CYP2C9, CYP2C19, CYP3A4 és CYP2D6 enzimekkel ......................................................................................................... 44 V.2.2. A quercetin konjugátumok kölcsönhatásai CYP2C19, CYP3A4 és CYP2D6 enzimekkel ......................................................................................................................... 46 1 V.3. Chrysin és quercetin konjugátumok kölcsönhatásai xantin-oxidáz enzimmel ........ 48 V.3.1. Chrysin és konjugátumainak kölcsönhatásai xantin-oxidáz enzimmel ............. 48 V.3.2. Quercetin és konjugátumainak kölcsönhatásai xantin-oxidáz enzimmel ......... 50 VI. Megbeszélés, következtetések ............................................................................................ 56 VI.1. Chrysin és konjugátumainak kölcsönhatásai humán szérum albuminnal ............. 56 VI.2. A chrysin és quercetin konjugátumok kölcsönhatásai CYP enzimekkel ................ 57 VI.3. Chrysin és quercetin konjugátumok kölcsönhatásai xantin-oxidáz enzimmel ...... 60 VII. Összefoglalás ...................................................................................................................... 64 VIII. Új megállapítások ............................................................................................................ 65 IX. Irodalomjegyzék ................................................................................................................. 66 X. Saját közlemények listája: ................................................................................................... 89 X.1. Az értekezés alapjául szolgáló folyóiratcikkek: .......................................................... 89 X.2. Az értekezés alapjául szolgáló kongresszusi előadások és poszter prezentációk: ... 90 X.3. Egyéb folyóiratcikkek: .................................................................................................. 91 X.4. Egyéb prezentációk: ...................................................................................................... 93 XI. Köszönetnyilvánítás ............................................................................................................ 94 2 Rövidítések jegyzéke 4’-OH-diclofenac 4’-hydroxydiclofenac 4-OH-mephenytoin 4-hydroxymephenytoin 6β-OH-testosteron 6β-hydroxytestosteron 6-MP 6-mercaptopurin AMP adenozin-monofoszfát APU allopurinol BCRP breast cancer resistance protein CHR chrysin COMT catechol-O-metil-transzferáz CYP citokróm P450 C7G chrysin-7-glükuronid C7S chrysin-7-szulfát FDA U.S. Food and Drug Administration DMSO dimetil-szulfoxid G6P glükóz-6-foszfát GMP guanozin-monofoszfát HPLC nagyhatékonyságú folyadékkromatográfia HSA humán szérum albumin IMP inozin-monofoszfát IR isorhamnetin I3G isorhamnetin-3-glükuronid Keap1 kelch-like ECH-associated protein 1 QUI quinidin MRP multi-drug-resistance associated protein NAD+/NADH nikotinamid-adenin-dinukleotid NADP+/NADPH nikotinamid-adenin-dinukleotid-foszfát NAP naproxen Nrf2 nuclear factor erythroid 2-related factor 2 OAT szerves anion transzporter OATP szerves anionokat transzportáló polipetid OXI oxipurinol 3 PBS phosphate buffered saline P-gp P-glikoprotein Q quercetin Q3’S quercetin-3’-szulfát Q3G quercetin-3-glükuronid SGLT1 Na+-függő glükóz transzporter 1 SULF sulfaphenazol SULT szulfotranszferáz TAM tamarixetin TIC ticlopidin UGT uridin-difoszfát glükuronil-transzferáz WAR warfarin XMP xantozin-monofoszfát XO xantin-oxidáz 4 I. Bevezetés A chrysin és a quercetin a természetben gyakran előforduló flavonoid aglikonok melyek számos növényben, gyümölcsben és zöldségben előfordulnak, emellett több étrend-kiegészítőben is extrém magas mennyiségben megtalálhatók. Mint a legtöbb flavonoid esetében, a chrysin és a quercetin orális biohasznosulása alacsony, ami a vegyületek alacsony vízoldhatóságával, valamint jelentős preszisztémás eliminációjával magyarázható. A chrysin biotranszformációja során főként szulfát és glükuronid metabolitok, míg a quercetin esetén metil származékok is képződnek. A normál étrenddel a flavonoidok és konjugátumaik együttes plazmakoncentrációja a nmol/L-es skálán mozog, de extrém bevitel esetén akár a több µmol/L-es értéket is elérhetik. A szakirodalom alapján a chrysin és a quercetin számos fehérjével (pl. szérum albumin, biotranszformációs enzimek, transzporterek) képesek kölcsönhatásba lépni. Azonban a metabolitok kapcsán – melyek jellemzően jóval magasabb koncentrációkat érnek el a szisztémás keringésben az anyavegyülethez képest – viszonylag kevés információ áll rendelkezésre. Ezért doktori képzésem során a chrysin és a quercetin fő konjugált metabolitjainak interakcióit vizsgáltam humán szérum albuminnal, valamint citokróm P450 és xantin-oxidáz enzimekkel. Kutatási eredményeink rávilágítanak, hogy nemcsak az aglikonok, de konjugált metabolitjaik is képesek kölcsönhatásba lépni albuminnal és biotranszformációs enzimekkel. Mivel a chrysin és/vagy a quercetin extrém magas bevitele befolyásolhatja az együttesen szedett gyógyszerek farmakokinetikai tulajdonságait, a magas flavonoid tartalmú étrend-kiegészítők gyógyszerekkel történő együttes alkalmazása fokozott elővigyázatosságot igényel. 5 II. Irodalmi áttekintés II.1. Humán szérum albumin A humán szérum albumin (HSA) a keringésben legnagyobb mennyiségben megtalálható plazmaprotein (Yamasaki és mtsai., 2013). A HSA
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