Development and validation of a liquid chromatography–mass spectrometry (LC–MS) assay for the determination of the anti-cancer agent N
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- 作者：Pradeep B. Lukka ; Philip Kestell ; James W. Paxton ; Bruce C. Baguley
- 关键词：SN 28049 ; LC– ; MS ; Pharmacokinetics ; Cancer ; Topoisomerase poison
- 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
- 出版年：2008
- 出版时间：15 November 2008
- 年：2008
- 卷：875
- 期：2
- 页码：368-372
- 全文大小：299 K
文摘
N-[2-(Dimethylamino)ethyl]-2,6-dimethyl-1-oxo-1,2-dihydrobenzo[b]-1,6-naphthyridine-4-carboxamide (SN 28049) is a potent topoisomerase II poison being developed to treat solid tumours. A reliable and sensitive LC–MS method has been developed and validated for the determination of SN 28049 in plasma using a structurally similar internal standard. This method had acceptable intra- and inter-assay accuracy (95–105 % ) and precision (R.S.D. < 6.5 % ) over the range 0.062–2.5 bc;M (using a 100 bc;l sample), and had a lower limit of quantitation of 0.062 bc;M. Both aqueous and plasma solutions of SN 28049 were stable during short-term (24 h at room temperature or 4 °C) and long-term storage (8 months at −80 °C), and following freezing and thawing (three cycles). The method was applied to study the pharmacokinetics of SN 28049 in mice after iv administration (8.9 mg/kg; n = 3 mice per time point). The maximum plasma concentration achieved was 1.22 ± 0.05 bc;M, and concentrations were measurable up to 12 h post-administration. A bi-exponential concentration-time curve was observed with an elimination half-life of 2.3 ± 0.2 h (mean ± S.E.), a volume of distribution of 34.5 ± 2.2 l/kg, and a plasma clearance of 12 ± 0.5 l/h/kg.