Two surface-active formulation ingredients, a water-soluble derivative of vitamin E (D-alpha-tocopherol polyethylene glycol 1000 succinate, vitamin E-TPGS) as well as a polyethoxylated derivative of 12-hydroxy-stearic acid (Solutol HS 15) were investigated in rats for their potential to increase the oral bioavailability of the p-glycoprotein (p-gp) and cytochrome P450 substrate colchicine. D-alpha-Tocopherol polyethylene glycol 1000 succinate and the polyethoxylated derivative of 12-hydroxy-stearic acid will be referred to as "surfactant 1" and "surfactant 2" in the following. Colchicine was administered to the animals at a dose level of 5 mg/kg in each 10% surfactant containing formulation. A solution of colchicine in isotonic saline was selected as a reference formulation. It was found that the administration of colchicine in the surfactant containing formulations resulted in significantly higher systemic exposures as compared to the aqueous reference vehicle (2-fold increase in AUC in the presence of surfactant 1 and 4-fold increase in AUC in the presence of surfactant 2). The aqueous solubility of colchicine was about 16.7 mg/ml, and the increase in solubility in the presence of 1% surfactant 1 or surfactant 2 to about 20.5 and 18.5 mg/ml was not considered to significantly affect the oral bioavailability. In summary, it was demonstrated that both surfactants are suitable formulation ingredients to improve the systemic exposure of colchicine in the rat. Due to the high aqueous solubility of colchicine the most likely reasons for these findings are inhibition of p-gp and/or metabolism as well as permeability enhancement by interactions of the surfactants with the intestinal membrane.
The metabolic profile of BAL4815, an antifungal azole drug, was determined using in vitro rat hepatocyte incubations and subsequent analysis by capillary LC-qTof-MS and MS/MS including accurate mass determination. For the detection of the metabolites, a mixture of the drug and its deuterium-labelled analogue was used for incubations. Metabolic stability of BAL4815 was high in cultured rat hepatocytes. However, several low-abundant metabolites were detected by the use of capillary LC-qTof-MS and manual investigation of the data. The peak intensity of the most abundant metabolite was close to the limit of detection. Except for an apparent oxidation product, the masses of the other detected metabolites could not be assigned to a single and frequently occurring biotransformation. Accurate mass determination and possible elemental compositions suggested that metabolism occurred through a combination of glutathionylation and defluorination. This was verified using accurate mass MS/MS. The use of accurate mass measurements and the derived suggestions for the elemental compositions were essential to elucidate this atypical metabolic pathway. A mass accuracy better than 8 ppm could be achieved for most assigned MS and MS/MS signals with intensities less than 6 cps in the spectra.
The in vitro metabolic pattern of BAL19403, a novel macrolide antibiotic, was investigated by capillary liquid chromatography/quadrupole time-of-flight mass spectrometry (LC/QTOF-MS) in incubations with human microsomes. For the elucidation of the metabolic pathway, BAL19403 labeled with four deuterium atoms (D4) was used, and detection of metabolites performed using mixtures of the unlabeled (H4) BAL19403 and its D4 analogue (1:1) as substrate. All metabolites appeared with similar chromatographic behavior. MS/MS spectra of BAL19403 and its metabolites are dominated by non-informative fragment ions. Therefore, the structure of the metabolites was elucidated mainly by accurate mass measurements with subsequent proposals of elemental compositions. Main biotransformations were N-demethylation, lactone ring hydrolysis, and oxidation. Additionally, N-dealkylation of the aromatic moiety was identified. This dealkylation results not only in formation of an aldehyde, according to the classical pathway, but also in formation of the corresponding alcohol and carboxylic acid. Final elucidation of their structures was possible, since this dealkylation takes place vicinal to the deuterium-labeled part of BAL19403 and interferes with D/H exchange. The degree of D/H exchange, determined by analysis of the metabolite isotopic pattern, was used to elucidate the adjacent functional group.
Background: BAL27862 is a synthetic small molecule, potently inducing apoptosis in cancer cells through tubulin depolymerization characterized by a unique microtubule phenotype. BAL27862 has demonstrated a broad in vitro anti-proliferative activity against a range of human tumor histotypes (low nM IC50s). Significant antitumor responses occur in animal models of human cancer after oral or intravenous (i.v.) administration, including tumors refractory to conventional treatments. The purpose of this study was to investigate the tissue distribution of BAL27862 in tumor-bearing mice. Tumor and brain penetration, together with anti-proliferative activity in glioblastoma (GBM) cell lines, is described. Materials and Methods: Anti-proliferative activity and induction of tumor cell death in vitro were analyzed using the YO-PRO® assay (48h incubation). CD1 nu/nu female mice were implanted with human colon carcinoma SW480 cells. For pharmacokinetic studies, tumor-bearing (approx. 150 mm3) mice were administered i.v. with either 2 mg/kg 14C-BAL27862 (n=6, single dose) or 8 mg/kg cold BAL27862 (n=33, once-weekly during 4 weeks). Animals were culled at serial time points. Radioactivity was measured in slices, with Bio-Imaging Analyzer read-outs of the exposed phosphor imaging plates quantified with Aida software. Cold BAL27862 was determined in plasma, brain and tumors using a specific LC-MS/MS method after sample homogenization and protein precipitation. Results: BAL27862 elicited a potent anti-proliferative activity in 6 GBM cell lines (IC50 range: 10–20nM), which was independent of PTEN status. Strikingly, at optimal concentrations, a dramatic loss of cell viability was observed (% cell death at 50nM BAL27862: >15% in 5 lines, >30% in 2 lines), demonstrating that BAL27862 potently drives GBM cells into a cell death program..In mice, after i.v. administration of 14C-BAL27862, radioactivity was distributed to all organs: notably brain and tumor. A delayed peak was observed in slowly perfused organs such as skin, tumor and fat-tissue. There was no tissue-specific retention of radioactivity, as halflives were comparable between tissues and blood. 48h after administration, radioactivity was almost undetectable in most tissues. Following administration of 8 mg/kg i.v. cold BAL27862 to mice, the excellent brain and tumor penetration was confirmed. Specifically, similar levels of BAL27862 were found in brain and plasma (Cmax of 6.86 µg/g and 7.34 µg/mL, respectively). The ratio tumor/plasma was also around 1. There was no brain or tumor accumulation over time, as concentrations paralleled those in plasma. Conclusions: BAL27862 is efficiently distributed to tissues and tumor in a mouse model of human cancer. Significant brain penetration, coupled with cytotoxic activity in GBM tumor cell lines, would support further evaluation of BAL27862 for the treatment of human brain cancers. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C233.
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