Development of a new method for the quantitation of metabolites in the absence of chemically synthetized authentic standards

Altares, Raquel; Pino, Francisco M Marquez Del; Benedit, Gonzalo; Guillén, María José; Cuevas, Carmen; Cruz, Mejia; Avilés, Pablo

doi:10.1016/j.jpba.2019.01.027

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“…Lurbinectedin, as well as reference standards for primary metabolites namely, N-Desmethyl-6-Hydroxy-lurbinectedin (Metabolite 1; coded as PM030036), 6-Hydroxylurbinectedin (Metabolite 2; coded as PM01158), N-Desmethyl-lurbinectedin (Metabolite 6; coded as PM030047), and 14'-Dehydroxy-lurbinectedin (Metabolite 7; coded as PM030779), as well as for the impurity 8',11'-Dioxo-lurbinectedin (coded as PM080323) were synthetized by PharmaMar S.A. (Colmenar Viejo, Spain); the metabolite 1',3'-Desmethylene-lurbinectedin (or Metabolite 4) was obtained by the method described elsewhere (Altares et al, 2019). 14 C-lurbinectedin (specific activity, 54 μCi/mg; radiochemical purity, 92.2%, coded as PM100567) labeled at substituted C4 indole (Fig.…”

Section: Test Articlesmentioning

confidence: 99%

Metabolic Disposition of Lurbinectedin, a Potent Selective Inhibitor of Active Transcription of Protein-Coding Genes, in Nonclinical Species and Patients

et al. 2022

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Lurbinectedin is a novel and potent selective inhibitor of active transcription of proteincoding genes, triggering apoptosis of cancerous cells, which has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Different studies aimed at exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rat, nonhuman primate (NHP) and human was determined as 23.4%, 29.8% and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, human), albumin and -1-acid glycoprotein (both from human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism (in 10 minutes, an 80% of the compound is metabolized in human), with CYP3A4 being the isoform involved in that metabolism; results also showed NHP being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHP (male only) and patients (both genders) demonstrated that the principal route of excretion of 14 C-lurbinectedin-related radioactivity was through the feces (88.7±10.1% in patients), with only a minor fraction recovered from the urine (5.6±2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95±3.1% and 70.2±10.9% in NHP and human, respectively); plasma metabolic profiling demonstrated the major (% compared to unchanged compound) circulating metabolites were N-Desmethyllurbinectedin (0.4±0.2% and 10.4±2.2% in NHP and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9±0.7% and 14.3±10.4% in NHP and patients, respectively).

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Section: Test Articlesmentioning

confidence: 99%