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Abstract: A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the quantitative determination of cabazitaxel, a novel tubulin-binding taxane, in 100μl aliquots of human lithium heparinized plasma with deuterated cabazitaxel as internal standard. The sample extraction and cleaning-up involved a simple liquid–liquid extraction with 20μl aliquots of 4% ammonium hydroxide, 100μl aliquots of acetonitrile and 1ml aliquots of n-butylchloride. Chromatographic separations were achieved on a reversed phase C18 column eluted at a flow-rate of 0.20ml/min on a gradient of acetonitrile. The overall cycle time of the method was 5min, with cabazitaxel eluting at 3.0min. The multiple reaction monitoring transitions were set at 836>555 (m/z), and 842>561 (m/z) for cabazitaxel and the internal standard, respectively. The calibration curves were linear over the range of 1.00–100ng/ml with the lower limit of quantitation validated at 1.00ng/ml. The within-run and between-run precisions, also at the level of the LLQ, were within 8.75%, while the accuracy ranged from 88.5 to 94.1%. As dilution of samples prior to extraction resulted in a loss of cabazitaxel of approximately 6.5% per dilution step, a second calibration curve ranging from 40.0 to 4000ng/ml was validated and was also linear. The within-run and between-run precisions in this range were within 4.99%, while the accuracy ranged from 95.8 to 100.3%. The method was successfully applied to samples derived from a clinical study. [Copyright &y& Elsevier]

Abstract: 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 200μl were purified by liquid–liquid extraction with 1ml n-hexane/isopropanol, after deproteination through addition of 50μl acetone and 50μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC® BEH C18 1.7μm 2.1mm×100mm column eluted at a flow-rate of 0.300ml/min on a gradient of 0.2mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10min, with elution times of 2.9, 3.0, 4.1 and 4.2min 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 5.00nM for tamoxifen and N-desmethyl-tamoxifen and 0.500nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187ng/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. [Copyright &y& Elsevier]

Abstract: A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the quantitative determination of RBG-286638, a novel multi-targeted protein kinase inhibitor, in 200μl aliquots of human potassium EDTA plasma with deuterated RGB-286638 as internal standard. The sample extraction and cleaning-up involved a simple liquid–liquid extraction with 100μl aliquots of acetonitrile and 1ml aliquots of n-butylchloride. Urine was accurately 5- and 10-fold diluted in blank plasma prior to extraction. Chromatographic separations were achieved on a reversed phase C18 column eluted at a flow-rate of 0.250ml/min on a gradient of 0.2mM ammonium formate and acetonitrile both acidified with 0.1% formic acid. The overall cycle time of the method was 7min, with RGB-286638 eluting at 1.9min. The multiple reaction monitoring transitions were set at 546>402 (m/z), and 549>402 (m/z) for RGB-286638 and the internal standard, respectively. The calibration curves were linear over the range of 2.00 to 1000ng/ml with the lower limit of quantitation validated at 2.00ng/ml. The within-run and between-run precisions were within 7.90%, while the accuracy ranged from 92.2% to 99.7%. The method was successfully applied to samples derived from a clinical study. [Copyright &y& Elsevier]