In Vitro and In Vivo Metabolism of a Selective ␦-Opioid Receptor

ABSTRACT: 4-({4-[(2-Hydroxy-ethyl)-methyl-carbamoyl]-phenyl}-quinolin-8-ylmethylene)-1-thiazol-4-ylmethyl-piperidinium (compound I) is a selective agonist of ␦-opioid receptor developed for the treatment of depressive and anxiety disorders. The in vitro biotransformation studies using rat, dog, and human hepatocytes showed that the metabolites detected in human hepatocytes were also found in either rat or dog hepatocytes. M1 (N-dealkylation), M2 (Ndemethylation), and M4 (carboxylic acid metabolite) were major phase I metabolites observed in all three species. Human CYP3A4/5 isoenzymes were identified to be the primary enzymes responsible for the formation of M1 and M2 in human liver microsomes. After single oral administration of [ 14 C]compound I, the major elimination route for [ 14 C]compound I and its metabolites in rat was through feces with 92.9% recovery. The results from the bile duct-cannulated study revealed that a minimum of 51% of administered dose was absorbed in rats. The pharmacokinetic analysis using unlabeled parent drug showed that compound I was rapidly absorbed and exhibited a mean apparent terminal half-life of approximately 2.7 h. A total of 15 metabolites of compound I were detected and profiled in rat urine, bile, and feces. In rat bile, compound I accounted for <1.5% of the excreted dose, suggesting that compound I underwent extensive metabolism before elimination. The structures of metabolites were elucidated by highresolution tandem mass spectrometry. M1, M4, and M6 were the most abundant metabolites observed in rat bile. Only a low level of parent [ 14 C]compound I was observed in rat plasma

Enhancing Nanoparticle-Based Visible Detection by Controlling the Extent of Aggregation

Visible indication based on the aggregation of colloidal nanoparticles (NPs) is highly advantageous for rapid on-site detection of biological entities, which even untrained persons can perform without specialized instrumentation. However, since the extent of aggregation should exceed a certain minimum threshold to produce visible change, further applications of this conventional method have been hampered by insufficient sensitivity or certain limiting characteristics of the target. Here we report a signal amplification strategy to enhance visible detection by introducing switchable linkers (SLs), which are designed to lose their function to bridge NPs in the presence of target and control the extent of aggregation. By precisely designing the system, considering the quantitative relationship between the functionalized NPs and SLs, highly sensitive and quantitative visible detection is possible. We confirmed the ultrahigh sensitivity of this method by detecting the presence of 20 fM of streptavidin and fewer than 100 CFU/mL of Escherichia coli

In vitro and in vivo metabolism of a selective δ -opioid receptor agonist

The results from the bile duct-cannulated study revealed that a minimum of 51% of administered dose was absorbed in rats. The pharmacokinetic analysis using unlabeled parent drug showed that Compound I was rapidly absorbed and exhibited a mean apparent terminal half-life of approximately 2.7 h. A total of 15 metabolites of Compound I were detected and profiled in rat urine, bile, and feces. In rat bile, Compound I accounted for <1.5% of the excreted dose, suggesting that Compound I underwent extensively metabolism before elimination. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. M1, M4, and M6 were the most abundant metabolites observed in rat bile. Only low level of parent [ 14 C]-Compound I was observed in rat plasma. DMD #40980