Avaliação pré-clínica do perfil farmacocinético do protótipo antitumoral lLQFM030 em ratos por LC-MS/MS

• Autor(a) principal: Zoghaib, Iury Valentim Jorge
• Data de Publicação: 2013
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFG
• dARK ID: ark:/38995/001300000591p
• Texto Completo: http://repositorio.bc.ufg.br/tede/handle/tede/3469
• topic: LQFM030; LC-MS/MS; Farmacocinética pré-clínica; LQFM030; LC-MS/MS; Preclinical pharmacokinetics; FARMACIA::FARMACOTECNIA

The LQFM030 was obtained by molecular simplification of nutlins (inhibitors of p53-MDM2 interaction) and, having demonstrated excellent antineoplastic activity in vitro (cytotoxicity against K-562 cell line with IC50 = 23 M) and in vivo against Ehrlich ascitic tumor with increased survival in treated animals developed the pharmacokinetic study of p.o. in rats. It was used for LC-MS/MS analytical method (Applied Biosystems MDS Sciex API 3200) previously validated together. O LQFM030 was administered to 3 rats (mean weight 186g) in predetermined dose of 100 mg/kg by gavage. After administration, samples were collected from 1.0 mL of blood by cannulation of the left jugular vein with heparinized syringe, the intervals 0-8 h. The blood samples were identified and centrifuged to obtain plasma which was frozen at -20°C until analysis. The kinetic parameters were calculated in the software WinNonlin 5.0 (Pharsight™). Results (mean ± SD) half-life (t1/2) 3.61 ± 0.68 h, total clearance (CLT) 36.49 ± 2.23 mL/min/kg, volume of distribution (Vd) 11,40 ± 1.58 L/kg. The LQFM030 had low value of t1/2, Vd high and high value of CLT. These values allow us to understand that the prototype study demonstrated a good safety profile of tissue distribution and/or has been extensively eliminated. When compared with the kinetic parameters obtained in other studies, it was observed difference in results is justified by the high interspecies variability, mainly in basal metabolic rate and body weight, once the route of administration, orally and intraperitoneally, are kinetically similar.