Development and validation of a sensitive solid-phase extraction and high-performance liquid chromatographic assay for the novel bio-reductive anti-tumor agent RH1 in human and mouse plasma

被引:7
作者
Khan, P [1 ]
Abbas, S [1 ]
Hargreaves, RHJ [1 ]
Caffrey, R [1 ]
Megram, V [1 ]
McGown, A [1 ]
机构
[1] Christie Hosp NHS Trust, Paterson Inst Canc Res, Sect Drug Dev & Imaging, Manchester M20 4BX, Lancs, England
来源
JOURNAL OF CHROMATOGRAPHY B | 1999年 / 729卷 / 1-2期
关键词
RH1;
D O I
10.1016/S0378-4347(99)00177-2
中图分类号
Q5 [生物化学];
学科分类号
071010 ; 081704 ;
摘要
A HPLC assay and solid-phase extraction technique from human plasma has been developed and validated for the experimental anticancer agent, RH1 (2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone) which is currently being evaluated by the CRC phase I/II committee. A 500 mg amino propyl solid-phase extraction cartridge was used to isolate RH1 from human plasma. Analysis was performed on a reversed-phase chromatography system using a 15 cm cyanopropyl column and isocratic elution with a 10% methanol-90% water (double distilled) solution. The lower limit of quantitation for RH1 was found to be 0.00375 mu g/ml (3.75 ng/ml+/-8.3%) in water and following extraction from plasma. Recovery of >80%(+/-11.9%) was achieved over a five-day validation study. This method was used to carry out pre-clinical studies in BDF mice (standard strain of hybrid mice) at three dose levels (2, 5 and 10 mg/kg of RH1 in 0.9% (w/v) saline via an intraperotoneal injection). Standard Version of PC Winnonlin pharmacokinetic modelling software was used to model the data. A none-compartmental model was used to describe the disposition of RH1 in mice plasma. RH1 was rapidly eliminated from plasma with a mean plasma clearance of 23.4 ml/min, mean volume of distribution of 321.6 ml and mean t(1/2), alpha and beta decays of 4.8 and 9.6 min, respectively. RH1 in human and mouse whole blood and plasma was found to be stable up to 2 h. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:287 / 295
页数:9
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