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In vitro bioactivation of bazedoxifene and 2-(4-hydroxyphenyl)-3-methyl-1Hindol- 5-ol in human liver microsomes
Trdan Lušin, Tina (Avtor), Tomašič, Tihomir (Avtor), Trontelj, Jurij (Avtor), Mrhar, Aleš (Avtor), Peterlin-Mašič, Lucija (Avtor)

URLURL - Predstavitvena datoteka, za dostop obiščite http://www.sciencedirect.com/science/article/pii/S0009279712000312?v=s5 Novo okno

Izvleček
Bazedoxifene is a selective estrogen receptor modulator (SERM) that has been developed for use in post-menopausal osteoporosis. However, it contains a potentially toxic 5-hydroxy-3-methylindole moiety. Previous studies on the 5-hydroxyindole and the 3-alkylindole-containing drugs indometacine, zafirlukast and MK-0524 structural analogs have shown that they are bioactivated by cytochrome P450s through a dehydrogenation process to form quinoneimine or 3-methyleneindolenine electrophilic species. In the present study, bazedoxifene was synthesized and then evaluated, together with raloxifene and 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (13), a 3-methyl-5-hydroxyindole-based structural fragment of bazedoxifene, for its ability to form reactive electrophilic species when incubated with human liver microsomes (HLM) or recombinant CYP isozymes. We showed that bazedoxifene was bioactivated only in trace amounts with recombinant CYP isozymes. In contrast, the N-dealkylated fragment of bazedoxifene (2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) was bioactivated in considerable amounts to an electrophilic intermediate, which was trapped with glutathione and identified by LC-MS/MS. This suggests that bazedoxifene would require initial N-dealkylation, which could subsequently lead to the formation of the reactive intermediate. However, such an N-dealkylated metabolite of bazedoxifene was not detected after the incubation of bazedoxifene in HLM or recombinant CYP isozymes.

Jezik:Angleški jezik
Ključne besede:bazedoksifen, raloksifen, LC-MS/MS, citokrom P450, osteporoza
Vrsta gradiva:Delo ni kategorizirano (r6)
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Leto izida:2012
Št. strani:str. 8-15
Številčenje:Vol. 197, issue 1
UDK:615.2
ISSN pri članku:0009-2797
DOI:10.1016/j.cbi.2012.03.001 Povezava se odpre v novem oknu
COBISS.SI-ID:3213425 Povezava se odpre v novem oknu
Število ogledov:699
Število prenosov:86
Metapodatki:XML RDF-CHPDL DC-XML DC-RDF
 
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Gradivo je del revije

Naslov:Chemico-biological interactions
Skrajšan naslov:Chem.-biol. interact.
Založnik:Elsevier
ISSN:0009-2797
COBISS.SI-ID:1720335 Novo okno

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