Development and validation of a liquid chromatography–tandem mass spectrometry method for the determination of ARQ 501 (β-lapachone) in plasma and tumors from nu/nu mouse xenografts
详细信息 查看全文
- 作者：R.E. Savage ; T. Hall ; K. Bresciano ; J. Bailey ; M. Starace ; T.C.K. Chan
- 关键词：β ; -Lapachone ; LC– ; MS/MS ; Electrospray ionization ; HPLC ; Pharmacokinetics ; Mouse plasma ; Mouse tumor
- 刊名：Journal of Chromatography B, Analytical Technologies in the Biomedical and Life Sciences
- 出版年：2008
- 出版时间：1 September 2008
- 年：2008
- 卷：872
- 期：1-2
- 页码：148-153
- 全文大小：171 K
文摘
A sensitive and specific LC–MS/MS method employing positive electrospray ionization for the determination of ARQ 501 (β-lapachone) in (nu/nu) mouse plasma and tumor tissue is described. Samples were processed using protein precipitation with acetonitrile. A d6 analog of ARQ 501 was used as the internal standard (IS). The analytes were separated using a Zorbax SB8 column (30 mm × 2.1 mm i.d. 5 μm particle size) and analyzed in the multiple reaction monitoring (MRM) mode using mass transitions of 243 > 159 and 249 > 159 m/z for ARQ 501 and d6-ARQ 501, respectively. The lower limit of quantitation (LLOQ) for ARQ 501 was 3.0 ng/mL. The calibration curve was linear in the range of 3.0–2000 ng/mL with a correlation coefficient better than 0.99. Intra- and inter-batch precisions were within 8.4 % for plasma and 11.8 % for tumor samples. Accuracy expressed as percentage relative error ( % R.E.) ranged from −9.0 to 7.7 for both plasma and tumor samples. Recovery was between 106 and 113 % for both ARQ 501 and its d6 analog. Plasma pharmacokinetic data of ARQ 501 in mouse from intraperitoneal (IP) dosing at 60 mg/kg obtained using this validated method is presented along with tumor concentration data. The Cmax, AUC(0−∞), t1/2, Cl/F, and Vd/F were determined to be 4016 ng/mL, 4392 h ng/mL, 3.9 h, 13.7 L/h/kg, and 76.5 L/kg, respectively. Tumor tissue concentrations were in the range 1–2 μM for approximately 2 h post-dose.