Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Erve, John C. L.; Vashishtha, S. C.; Ojewoye, O.; Adedoyin, Adedayo; Espina, Robert; DeMaio, William; Talaat, Rasmy E.

doi:10.1080/00498250802001826

Cited by 25 publications

(22 citation statements)

References 23 publications

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“…3. Erve et al 64 reported the fragmentation pathway of prazosin that is in agreement with ours. The major structural difference is the fragment peak at 231 m/z.…”

Section: Molecules With Single Structural Domainsupporting

confidence: 90%

Automated molecular formula determination by tandem mass spectrometry (MS/MS)

Jarussophon

Acoca

Gao

et al. 2009

Analyst

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Automated software was developed to analyze the molecular formula of organic molecules and peptides based on high-resolution MS/MS spectroscopic data. The software was validated with 96 compounds including a few small peptides in the mass range of 138-1569 Da containing the elements carbon, hydrogen, nitrogen and oxygen. A Micromass Waters Q-TOF Ultima Global mass spectrometer was used to measure the molecular masses of precursor and fragment ions. Our software assigned correct molecular formulas for 91 compounds, incorrect molecular formulas for 3 compounds, and no molecular formula for 2 compounds. The obtained 95% success rate indicates high reliability of the software. The mass accuracy of the precursor ion and the fragment ions, which is critical for the success of the analysis, was high, i.e. the accuracy and the precision of 850 data were 0.0012 Da and 0.0016 Da, respectively. For the precursor and fragment ions below 500 Da, 60% and 90% of the data showed accuracy within #0.001 Da and #0.002 Da, respectively. The precursor and fragment ions above 500 Da showed slightly lower accuracy, i.e. 40% and 70% of them showed accuracy within #0.001 Da and #0.002 Da, respectively. The molecular formulas of the precursor and the fragments were further used to analyze possible mass spectrometric fragmentation pathways, which would be a powerful tool in structural analysis and identification of small molecules. The method is valuable in the rapid screening and identification of small molecules such as the dereplication of natural products, characterization of drug metabolites, and identification of small peptide fragments in proteomics. The analysis was also extended to compounds that contain a chlorine or bromine atom.

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“…3. Erve et al 64 reported the fragmentation pathway of prazosin that is in agreement with ours. The major structural difference is the fragment peak at 231 m/z.…”

Section: Molecules With Single Structural Domainsupporting

confidence: 90%

Automated molecular formula determination by tandem mass spectrometry (MS/MS)

Jarussophon

Acoca

Gao

et al. 2009

Analyst

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“…Microsomes with NADPH, UGDPA or GSH as cofactors could produce oxidized metabolites as well as glucuronide and GSH conjugates, but cryopreserved hepatocytes could not produce similar amounts of GSH conjugates and glucuronide conjugate patterns were dissimilar [123]. This is consistent with reported low levels of GSH in cryopreserved hepatocytes [124].…”

Section: Examples Of In Vitro-in Vivo Extrapolationsupporting

confidence: 72%

“…The GSH conjugate was proposed to result from a reactive intermediate that could be trapped by semicarbazide [122]. Subsequent in vivo studies in rats revealed three new Phase I metabolites and a glucose and a taurine conjugate were produced in addition to previously observed in vitro metabolites [123]. In addition, one oxidated and two glucuronated metabolites were quantitatively the most abundant metabolites in vivo, but of these only the other glucuronide conjugate was quantitatively a major metabolite in in vitro incubations [123].…”

Section: Examples Of In Vitro-in Vivo Extrapolationmentioning

confidence: 96%

“…Prazosin metabolism has also been recently studied in rats both in vitro and in vivo using a state-of-the-art TOF mass spectrometer [122,123]. Microsomes with NADPH, UGDPA or GSH as cofactors could produce oxidized metabolites as well as glucuronide and GSH conjugates, but cryopreserved hepatocytes could not produce similar amounts of GSH conjugates and glucuronide conjugate patterns were dissimilar [123].…”

Section: Examples Of In Vitro-in Vivo Extrapolationmentioning

confidence: 99%

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From Known Knowns to Known Unknowns: Predicting in Vivo Drug Metabolites

Pelkonen

Tolonen²,

Korjamo³

et al. 2009

Bioanalysis

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'It is better to be useful than perfect'. This review attempts to critically cover and assess the currently available approaches and tools to answer the crucial question: Is it possible (and if it is, to what extent is it possible) to predict in vivo metabolites and their abundances on the basis of in vitro and preclinical animal studies? In preclinical drug development, it is possible to produce metabolite patterns from a candidate drug by virtual means (i.e., in silico models), but these are not yet validated. However, they may be useful to cover the potential range of metabolites. In vitro metabolite patterns and apparent relative abundances are produced by various in vitro systems employing tissue preparations (mainly liver) and in most cases using liquid chromatography-mass spectrometry analytical techniques for tentative identification. The pattern of the metabolites produced depends on the enzyme source; the most comprehensive source of drug-metabolizing enzymes is cultured human hepatocytes, followed by liver homogenate fortified with appropriate cofactors. For specific purposes, such as the identification of metabolizing enzyme(s), recombinant enzymes can be used. Metabolite data from animal in vitro and in vivo experiments, despite known species differences, may help pinpoint metabolites that are not apparently produced in in vitro human systems, or suggest alternative experimental approaches. The range of metabolites detected provides clues regarding the enzymes attacking the molecule under study. We also discuss established approaches to identify the major enzymes. The last question, regarding reliability and robustness of metabolite extrapolations from in vitro to in vivo, both qualitatively and quantitatively, cannot be easily answered. There are a number of examples in the literature suggesting that extrapolations are generally useful, but there are only a few systematic and comprehensive studies to validate in vitro-in vivo extrapolations. In conclusion, extrapolation from preclinical metabolite data to the in vivo situation is certainly useful, but it is not known to what extent.

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“…M21, the N-glucoside was unusual. Animal N-glucoside metabolites are described for barbiturates [19] and anilines [20] but quaternary N-glucosides appear to only have been previously described in plant metabolism [21]. The speculative structure drawn for imiloxan M19 was consistent with the spectral data but was unprecedented in drug metabolism.…”

Section: Time-dependent Inhibitionmentioning

confidence: 60%

Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

Fitch¹,

Chen²,

Liu³

et al. 2010

DML

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Imiloxan is an alpha2 adrenoceptor antagonist and was developed for depression in the 1980's. In Phase 1 clinical trials imiloxan dosing led to hypersensitivity reactions; the molecule's development was discontinued. The present study revisits the in vitro metabolism of imiloxan using modern analytical methods. Human and rat liver microsomes convert imiloxan into a variety of metabolites many of which are unstable and or reactive. Imiloxan also yields high protein covalent binding in microsomal assays. Imiloxan is a useful test molecule for defining the relationship between liver covalent binding and idiosyncratic toxicity.

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Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS)

Cited by 25 publications

References 23 publications

Automated molecular formula determination by tandem mass spectrometry (MS/MS)

Automated molecular formula determination by tandem mass spectrometry (MS/MS)

From Known Knowns to Known Unknowns: Predicting in Vivo Drug Metabolites

Application of Modern Drug Metabolism Structure Determination Tools and Assays to the In Vitro Metabolism of Imiloxan

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