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

Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies 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 rats, nonhuman primates (NHP), and humans was determined as 23.4%, 29.8%, and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, and human), albumin, and α-1-acid glycoprotein (both human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism-in 10 minutes, 80% of the compound is metabolized in human-with CYP3A4 being the isoform involved in that metabolism. Results also showed NHPs being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHPs (male only), and patients (both genders) demonstrated that the principal route of excretion of 14C-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 NHPs and humans, respectively). Plasma metabolic profiling demonstrated the major (% compared with unchanged compound) circulating metabolites were N-Desmethyl-lurbinectedin (0.4% ± 0.2% and 10.4% ± 2.2% in NHPs and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9% ± 0.7% and 14.3% ± 10.4% in NHP and patients, respectively). SIGNIFICANCE STATEMENT: Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, and was recently approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. The present study provides a complete set of information on the pharmacokinetics, biotransformation, and elimination of 14C-lurbinectedin and its metabolites, following a single intravenous administration to nonclinical species (rats and nonhuman primates) and patients.

The effects of grape seed in the diet of the Penedes chicken, on growth and on the chemical composition and sensory profile of meat.

1. Effect of a diet with 5% grape seed inclusion, substituting for maize compared to a standard diet, was studied in the Penedes chicken. 2. A total of 128 chickens were used, half from each sex. Individual weights and feed intake were controlled weekly from the first d to 5th week and fortnightly until the 15th week. On the 16th week, chemical analyses of meat from 16 thighs from each diet and sex were carried out, as well as a sensory analysis of meat from 24 thighs. Differences between diet and sex were analysed using live body weight, feed intake, feed conversion rate (FCR), chemical composition and sensory attributes of the meat. 3. At the end of the experiment, no significant differences were observed on live body weight, feed intake and FCR due to diet. 4. Meat showed no differences due to diet in the percentages of protein, lipid and ash. 5. Meat from the grape seed diet showed a higher percentage of unsaturated fatty acids due to linoleic acid. It also showed a more nutty smell, a more metallic flavour and more stringiness. There was, also, less of a pork crackling odour and flavour, a less sweet flavour and less of a broiler meat flavour.

Metabolite profiling of the novel anti-cancer agent, plitidepsin, in urine and faeces in cancer patients after administration of 14C-plitidepsin.

PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi. METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC). RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces. CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.

Synthesis of ecteinascidin ET-743 and phthalascidin Pt-650 from cyanosafracin B.

An efficient new process is described for the synthesis of ecteinascidin ET-743 (1) and phthalascidin (2), starting from readily available cyanosafracin B (3).

Genetic parameters for egg number, egg weight, and eggshell color in three Catalan poultry breeds.

Heritabilities for egg number, egg weight, and eggshell color (percentage light absorbance) at 39 wk of age, and the genetic correlations between them were estimated by restricted maximum likelihood in three Catalan poultry breeds: Penedesenca Negra (PN), Prat Lleonada (PL), and Empordanesa Roja (ER). Additive genetic differences between these breeds were also estimated. Data were from the IRTA Poultry Genetic Conservation Program and consisted of records from 1,309 PN, 1,466 PL, and 1,440 ER hens, which were obtained from 80 contemporary batches per breed hatched between 1987 and 1992. Estimates of heritability for egg number, egg weight, and eggshell color were, 0.20, 0.59, and 0.49 for PN, 0.31, 0.48, and 0.53 for PL; and 0.33, 0.50, and 0.27 for ER. Estimated genetic correlations between egg number and egg weight, egg number and shell color, and egg weight and shell color were, for PN, -0.22, -0.03, and 0.00; for PL, -0.21, -0.06, and 0.09; and -0.19, -0.29, and 0.30 for ER. Heritability for eggshell color and genetic correlation between eggshell color and other traits showed a different genetic pattern in ER breed. Significant additive genetic differences (P < 0.05) were found between ER and PN base populations for egg number (3.89), egg weight (0.91), and eggshell color (-3.50); and between ER and PL for egg number (6.69) and eggshell color (35.39). The PN and PL breeds differed significantly (P < 0.05) for eggshell color (38.22), which was darker in PN. These results could be taken as the expected genetic differences for these breeds.

Identification of three single nucleotide polymorphisms in the chicken insulin-like growth factor 1 and 2 genes and their associations with growth and feeding traits.

The chicken insulin-like growth factor (IGF)1 and IGF2 genes have been partially sequenced in six individuals of each of two chicken strains of the Black Penedesenca breed (PN and MN). These two strains are genetically diverse for growth traits. Sequence alignment revealed the existence of three single nucleotide polymorphisms (SNP) (IGF1-SNP1, IGF2-SNP2, and IGF2-SNP3). These three SNP and a fourth IGF1 polymorphism (IGF1-SNP4) were typed in 60 individuals from each strain by using PCR-RFLP or primer extension analysis. No significant associations among these four SNP, growth traits, and plasma IGF1 concentration were identified. In contrast, suggestive associations (P < or = 0.05) were found between IGF1-SNP1 and average daily gain at 107 d and feed efficiency at 44, 73, and 107 d. However, these associations were not simultaneously found in both strains suggesting that they might have been produced by linkage disequilibrium with another mutation located in the IGF1 locus or another linked gene. Since the PN and MN strains differ very markedly on their feed intake, the chicken leptin gene was included in the sequence analysis. Unfortunately, attempts to amplify several regions of this gene were unsuccessful. Even when primers complementary to highly conserved regions were used, the PCR consistently failed. Other authors have reported similar problems when trying to amplify avian leptin sequences.

Fourier transform infrared spectroscopy indicates a major conformational rearrangement in the activation of rhodopsin.

The study of the structural differences between rhodopsin and its active form (metarhodopsin II) has been carried out by means of deconvolution analysis of infrared spectra. Deconvolution techniques allow the direct identification of the spectral changes that have occurred, which results in a significantly different view of the conformational changes occurring after activation of the receptor as compared with previous difference spectroscopy analysis. Thus, a number of changes in the bands assigned to solvent-exposed domains of the receptor are detected, indicating significant decreases in extended (beta) sequences and in reverse turns, and increases in irregular/aperiodic sequences and in helices with a non-alpha geometry, whereas there is no decrease in alpha-helices. In addition to secondary structure conversions, qualitative alterations within a given secondary structure type are detected. These are seen to occur in both reverse turns and helices. The nature of this spectral change is of great importance, since a clear alteration in the helices bundle core is detected. All these changes indicate that the rhodopsin --> metarhodopsin II transition involves not a minor but a major conformational rearrangement, reconciling the infrared data with the energetics of the activation process.