Određivanje flumazenila u serumu tečnom hromatografijom sa masenom spektrometrijom: primena u kinetičkoj studiji kod akutnog predoziranja diazepamom
Sažetak
Uvod/Cilj. Flumazenil je antagonist benzodiazepinskih receptora čiji su efekti ispitivani kod različitih indikacija kao što su reverzija sedacije posle hirurških intervencija ili dijagnostičkih procedura, terapija kome u akutnim trovanjima ili simptomatska terapija hepatične encefalopatije. Pojedini lekovi, kao što je teofilin, mogu dovesti do produženja poluvremena eliminacije flumazenila. Imajući u vidu dugo poluvreme eliminacije diazepama i njegovih metabolita, istovremena upotreba teofilina sa flumazenilom bi smanjila potrebu za ponovljenim davanjem flumazenila kod bolesnika sa akutnim trovanjem diazepamom. Stoga, cilj ovog rada bio je uvođenje pouzdane i precizne metode za određivanje koncentracije flumazenila u krvi nakon terapijske primene kod bolesnika sa akutnim trovanjem, a zatim, primenom ove metode utvrđivanje da li dolazi do izmena u kinetici flumazenila u prisustvu istovremeno primenjivanog aminofilina (kombinacija teofilina i etilendiamina u odnosu 2 : 1). Metode. Uzorci krvi bolesnika sa akutnim trovanjem diazepamom koji su dobili samo flumazenil u dozi od 0,5 mg ili istovremeno sa 3 mg/kg aminofilina, uzeti su 1, 3, 10, 30, 60, 120 i 240 min nakon njegove intravenske primene. Uzorci su pripremani čvrsto-faznom ekstrakcijom (SPE) na Oasis HLB kertridžima sa etilacetatom kao ekstrakcionim agensom. Flumazenil je određen tečnom hromatografijom sa masenom spektrometrijom (LC-MS) u single ion monitoring (SIM) modu na m/z 304. Razdvajanje flumazenila od komponenti matriksa izvršeno je na Lichrospher RP-8 koloni uz korišćenje smeše kiselog acetonitrila i 20 mM amonijum acetata u vodi (55 : 45) kao mobilne faze. Rezultati. Primenjena analitička metoda pokazala je odličan analitički prinos (94.65%). Dobijeni ekstrakti bili su čistiji nego ekstrakti dobijeni pomoću istog ekstraktanta nakon tečno-tečne ekstrakcije. Limit detekcije i limit kvantifikacije (LoQ) opisane LC-MS metode bili su 0,5 ng /mL i 1 ng/mL. Kod bolesnika lečenih istovremenom primenom flumazenila i aminofilina, konstanta eliminacije za flumazenil bila je značajno veća, a poluvreme eliminacije značajno duže u odnosu na ove parametre praćene u grupi bolesnika koja je primila samo flumazenil (p < 0,05). Zaključak. Primenjena LC-MS metoda za određivanje flumazenila u serumu bolesnika sa akutnim trovanjem diazepamom je brza, osetljiva, precizna i specifična. Istovremena primena teofilina značajno produžava eliminaciju flumazenila prilikom lečenja akutnih trovanja diazepamom.
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