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A rapid and sensitive LC–MS/MS method developed to quantify lurbinectedin in human plasma and urine.The assay has successfully been validated in the 0.1–100 and 1–1000ng/mL ranges.The assay was successfully applied for quantification of lurbinectedin in plasma and urine in a mass balance study.Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC–MS/MS) assay to quantify lurbinectedin in human plasma and urine. Plasma samples were pre-treated with 1M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns. Lurbinectedin was eluted from the columns using tert-butyl methyl ether (TBME). Urine was first diluted in plasma and lurbinectedin was extracted from this matrix by liquid-liquid extraction using TBME. Samples were measured by LC–MS/MS in the positive electron ion spray mode. The method was linear over 0.1–100ng/mL and 1–1000ng/mL in plasma and urine, respectively, with accuracies and precisions within ±15% (20% for LLOQ) and below 15% (20% for LLOQ), respectively. The method was developed to support a mass balance study in which patients received a dose of 5mg lurbinectedin.