Metabolism studies profiling

These in vivo and in vitro human metabolism studies indicate that pyrethroids undergo rapid metabolism and elimination as observed in rats, and qualitative metabolic profiles (e.g., kinds of metabolites) of pyrethroids are assumed to be almost the same between humans and rats, suggesting that a large database of animal metabolism of pyrethroids could provide useful information for the evaluation of behavior of pyrethroids in humans. Nowadays, human pesticide dosing studies for regulatory propose are severely restricted in the US, and thus detailed comparison of in vitro metabolism (e.g., metabolic rate constants of pathways on a step-by-step basis) using human and animal tissues could be an appropriate method to confirm the similarity or differences in metabolism between humans and animals. 

I. D. Wilson, J. K. Nicholson, J. Castro-Perez, J. H. Granger, K. A. Johnson, B. W. Smith, and R. S. Plumb. High Resolution Ultra Performance Liquid Chromatography Coupled to oa-TOF Mass Spectrometry as a Tool for Differential Metabolic Pathway Profiling in Functional Genomic Studies. J. Proteome Res., 4(2005) 591-598. 

Lung metabolism studies would greatly benefit from the availability of reliable in vitro experimental models that are able to reproduce biochemical and toxicological processes that occur in the human lung. Because of differences in the expression profiles of biotransformation enzymes between animal species, conclusions drawn from experimental animals may not be representative of what occurs in the human lung. 

A simple cyclic diester of carbonic acid is ethylene carbonate (7.96), a chemical with a toxicity profile resembling that of ethylene glycol (7.97). Metabolic studies have confirmed that ethylene carbonate is hydrolyzed very rapidly to ethylene glycol (whose oxidation is discussed in Chapt. 2 in [7]) and C02. Indeed, rats given an oral dose of ethylene carbonate did not excrete the unchanged xenobiotic in detectable amounts, and blood levels of the diester were ca. 100-fold smaller than those of ethylene glycol [178],... 

Exact mass is currently used in a range of application areas such as metabolism studies, impurity profiling, environmental analysis, synthetic chemistry (open access), industrial applications, clinical screening for drugs of abuse, and natural products, where rapid confirmation and low-level detection with high level of confidence are required. 

Kuehl, D., Gu, M., and Wang, Y. (2006). Comparing mass defect filtering and accurate mass profile extracted ion chromatogram (AMPXIC) for metabolism studies. In Proceedings of the 54th ASMS Conference on Mass Spectrometry and Allied Topics, Seattle, WA. 

High-sensitivity techniques for the quantitation and characterization of circulating metabolites following administration of radiolabeled compounds are of critical importance to understand the safety and efficacy profiles of novel drug candidates. AMS is one of the most sensitive techniques for the detection of radiolabeled components. However, the high cost and slow throughput of AMS analysis preclude the routine use of the techniques for metabolism studies. 

Nassar, A. E., and Lee, D. Y. (2007b). Novel radio-HPLC detector for sensitive metabolite profiling and structural elucidation in support of drug metabolism studies. Drug Metab. Rev. 39(Suppl. 1) 73. 

A non-ribosomal biosynthetic pathway is clearly indicated for cyclosporin A, considering the uncommon structural elements MeBmt, L-a-aminobutyric acid and D-alanine as well as the plethora of isolated congeners [20,21]. Non-ribosomal biosynthesis directed by multienzyme thiotemplates have been reported for other small peptides of microbial origin, for example, gramicidin S [22] and enniatin [23]. Experimental data for cyclosporin A were obtained by feeding appropriate labelled precursors to cultures of T. inflation strains. The distribution profile of the labelled atoms in cyclosporin A was determined by 3H- or 13C-NMR spectroscopy. In preliminary trials with several tritium and carbon-14 labelled precursors, [met/y>/-3H]methionine proved to be the most suitable marker for the biosynthetic preparation of radiolabelled cyclosporin A for pharmacokinetic and metabolic studies [24],... 

If metabolism in animal models is extensive or the generated metabolite(s) is shown to have toxic effects, in vitro metabolism studies using isolated P-450 isozymes, tissue homogenates containing the microsomal fraction, hepatocytes, and liver slices are commonly conducted to determine if the extent of metabolism and the metabolite profile is similar for animals and humans. The results from these in vitro metabolism comparison studies can be used to select the animal models for definitive development studies that have similar metabolism profiles to humans. 

In a cross-sectional study in 44 men, olanzapine had a worse metabolic risk profile than risperidone (444). The men (mean age 29 years) took olanzapine (n = 22 mean duration 18 months mean dose 13 mg/day) or risperidone (,n = 22 mean duration 17 months mean dose 2.8 mg/ day). Those who took olanzapine had significantly higher plasma triglyceride concentrations, significantly higher very low density lipoprotein cholesterol concentrations, a trend to a lower HDL cholesterol concentration, and a... 

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