Quantification of tamoxifen and three of its phase-I metabolites in human plasma by liquid chromatography/triple-quadrupole mass spectrometry

被引:36
作者
Binkhorst, Lisette [2 ]
Mathijssen, Ron H. J. [1 ]
Moghaddam-Helmantel, Inge M. Ghobadi [1 ]
de Bruijn, Peter [1 ]
van Gelder, Teun [2 ]
Wiemer, Erik A. C. [1 ]
Loos, Walter J. [1 ]
机构
[1] Univ Med Ctr, Daniel den Hoed Canc Ctr, Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands
[2] Univ Med Ctr, Erasmus MC, Dept Hosp Pharm, Rotterdam, Netherlands
关键词
Tamoxifen; N-desmethyl-tamoxifen; 4-Hydroxy-tamoxifen; Endoxifen; LC-MS/MS; BREAST-CANCER; QUANTITATIVE ASSAY; CYP2D6; GENOTYPE; ADJUVANT BREAST; VALIDATION; BIOTRANSFORMATION; INHIBITOR;
D O I
10.1016/j.jpba.2011.08.002
中图分类号
O65 [分析化学];
学科分类号
070302 ; 081704 ;
摘要
In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200 mu l were purified by liquid-liquid extraction with 1 ml n-hexane/isopropanol, after deproteination through addition of 50 mu l acetone and 50 mu l deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC (R) BEH C18 1.7 mu m 2.1 mm x 100 mm column eluted at a flow-rate of 0.300 ml/min on a gradient of 0.2 mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10 min, with elution times of 2.9, 3.0, 4.1 and 4.2 min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372 > 72 (m/z) for tamoxifen, 358 > 58 (m/z) for N-desmethyl-tamoxifen, 388 > 72 (m/z) for 4-hydroxy-tamoxifen and 374 > 58 (m/z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00 nM for tamoxifen and N-desmethyl-tamoxifen and 0.500 nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187 ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC-MS/MS method in serum. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:1016 / 1023
页数:8
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