A mass spectrometric approach to the identification of conjugated drug metabolites

Jacobs, Pauline; Delbressine, L. P. C.; Kaspersen, Frans M.; Schmeits, G. J. H.

doi:10.1002/bms.1200141121

Cited by 9 publications

(3 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…spectrometry appears to be the method of choice (Jacobs et al 1987). The identification of a glucuronide conjugate of the intermediate hydroxylamine of desmethylmianserin indicates that further oxidation at nitrogen might also occur.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Biotransformation of mianserin in laboratory animals and man

et al. 1992

Self Cite

View full text Add to dashboard Cite

1. The biotransformation and excretion of the antidepressant mianserin were studied after oral administration of the labelled drug to rats, mice, rabbits, guinea pigs and humans. Mianserin was well absorbed and almost completely metabolized in all five species. 2. Major metabolic pathways of mianserin were p-oxidation of the N-substituted aromatic ring followed by conjugation, and oxidation and demethylation of the N-methyl moiety, followed by conjugation. Direct conjugation of the N-methyl moiety was observed as a metabolic pathway specific for man. 3. Conjugated metabolites were isolated by h.p.l.c. and identified by 1H-n.m.r. and FAB spectrometry. Novel metabolites such as an N-O-glucuronide in the guinea pig and an N-sulphonate in rat and guinea pig, were identified using these techniques. A quaternary N-glucuronide was found only in man.

show abstract

Section: Discussionmentioning

confidence: 98%

“…assay method has been used for the direct isolation of urinary conjugates formed as metabolites of mianserin. Improved mass spectrometry (see Jacobs et al 1987) and 'H-n.m.r. techniques allowed us to obtain a more up-to-date appraisal of the metabolism of mianserin.…”

Section: Introductionmentioning

confidence: 99%

Biotransformation of mianserin in laboratory animals and man

et al. 1992

Self Cite

View full text Add to dashboard Cite

show abstract

“…12 The elimination of the dehydrodeoxyglucuronic acid to yield the protonated aglycone [ M C H 176 C ], formed by cleavage of the glycosidic bond and transfer of a proton from the glucuronic moiety to the aglycone, is a diagnostic ion for many glucuronides. 11,12 The protonated aglycone ion should be identical with the molecular ion of the corresponding unconjugated metabolites. Therefore, characteristic fragment ions or losses presented in the unconjugated metabolite spectra should recur in the spectra of the conjugated metabolites also.…”

Section: Metabolites With Authentic Synthetic Compounds Availablementioning

confidence: 99%

Metabolites of an orally active antimicrobial prodrug, 2,5‐bis(4‐amidinophenyl)furan‐bis‐O‐methylamidoxime, identified by liquid chromatography/tandem mass spectrometry

Zhou¹,

Thakker²,

Voyksner³

et al. 2004

J. Mass Spectrom.

View full text Add to dashboard Cite

DB75 (2,5-bis(4-amidinophenyl)furan) is a promising antimicrobial agent against African trypanosomiasis and Pneumocystis carinii pneumonia. However, it suffers from poor oral activity in rodent models for both infections. In contrast, a novel prodrug of DB75, 2,5-bis(4-amidinophenyl)furan-bis-O-methylamidoxime (DB289), has excellent oral activity. DB289 is currently undergoing clinical investigation as a candidate drug to treat primary stage African trypanosomiasis and Pneumocystis carinii pneumonia. In this study, metabolites of DB289 formed after incubation with freshly isolated rat hepatocytes were characterized using liquid chromatography/ion trap mass spectrometry. Administration of DB289 and octadeuterated DB289 in a 1 : 1 mixture greatly facilitated metabolite identification by providing isotope patterns with twin ions separated by 8 m/z units in the ratio 1 : 1, in the extracted ion chromatograms of molecular ions and in the product ion mass spectra of metabolites. Ten metabolites were identified. Series of O-demethylations and N-dehydroxylations led to the metabolic activation of DB289 to DB75 with the production of four intermediate phase I metabolites. Phase II glucuronidation and sulfation led to the formation of four glucuronide and one sulfate metabolites.

show abstract

Gas chromatography/negative chemical ionization mass spectrometry of intact glucuronides

Brown

Garland

Fukuda

1990

Biol. Mass Spectrom.

View full text Add to dashboard Cite

Gas chromatography-negative chemical ionization mass spectrometry (GC-NCIMS) has been applied to the analysis of 0-and S-glucuronides. The glucuronides were derivatized with pentafluorobenzyl (PFB) bromide and Tri-Sil, and analyzed by GC-NCIMS. All glucuronides gave a large [M-PFBI-ion indicative of the molecular weight of the compound. This methodology has been successfully applied to the identification of a glucuronide of unknown structure.

show abstract

A mass spectrometric approach to the identification of conjugated drug metabolites

Cited by 9 publications

References 25 publications

Biotransformation of mianserin in laboratory animals and man

Biotransformation of mianserin in laboratory animals and man

Metabolites of an orally active antimicrobial prodrug, 2,5‐bis(4‐amidinophenyl)furan‐bis‐O‐methylamidoxime, identified by liquid chromatography/tandem mass spectrometry

Gas chromatography/negative chemical ionization mass spectrometry of intact glucuronides

Contact Info

Product

Resources

About