Identification and human exposure prediction of two aldehyde oxidase-mediated metabolites of a methylquinoline-containing drug candidate.

1. Aldehyde oxidase (AO enzymes)-mediated oxidation predominantly occurs at a carbon atom adjacent to the nitrogen on aromatic azaheterocycles. In the current report, we identified that AO enzymes oxidation took place at both the C-2 and C-4 positions of the methylquinoline moiety of Compound A based on data from mass spectrometric analysis, AO enzymes "litmus" test, and comparison with authentic standards.

Structural identification of imatinib cyanide adducts by mass spectrometry and elucidation of bioactivation pathway.

Rationale: Recent publications have reported that imatinib forms cyanide and methoxylamine adducts in vitro but without detail structural identification. The current work reports the identification of seven cyanide adducts that elucidate the bioactivation pathways and may provide hints for observed clinical adverse effects of the drug.

Methods: Imatinib was incubated with human liver microsomal proteins in the presence of a NADPH-regeneration system and the trapping agents reduced GSH, potassium cyanide and methoxylamine.

Boronic acid-containing proteasome inhibitors: alert to potential pharmaceutical bioactivation.

Medicinal chemists try to avoid certain organic functional groups, summarized in an ever-growing list, in order to avoid the potential bioactivation to reactive metabolites. To add to that alert list, we report herein that boronic acid-containing compound structures, such as those found in proteasome inhibitors bortezomib and ixazomib, can become bioactivated to chemically reactive imine amide metabolites. Test compounds, ixazomib and bortezomib, were incubated in vitro using human liver fractions containing cytosol and microsomes (S9) under conventional conditions in the presence of GSH.

Update on hydrocodone metabolites in rats and dogs aided with a semi-automatic software for metabolite identification Mass-MetaSite.

1. There has been a lack of in vivo metabolite profiling update of hydrocodone since the original report on species differences was published in 1978. As such, the mechanism for its analgesic activity in different species has been ambiguous.

Identification of imine or enamine drug metabolites using online hydrogen/deuterium exchange and exact mass measurements.

Rationale: Drug metabolites that have imine or enamine partial structures cause extra mass-to-charge (m/z) increases in online hydrogen/deuterium exchange (HDX) in addition to hydroxyl or amine protons. Online HDX and exact mass measurement were used herein to characterize this extra increase property, and to further confirm proposed metabolite structures.

Methods: Metabolites of two proprietary compounds as well as two commercially available compounds were analyzed using aqueous and HDX liquid chromatography coupled with an LTQ-Orbitrap.

Metabolic profile of [(14)C]bendamustine in rat urine and bile: preliminary structural identification of metabolites.

Bendamustine, a bifunctional alkylating agent, is currently in clinical trials for the treatment of hematological and other malignancies. Although it has been used in the former East Germany for more than 30 years, very limited information is available on its biotransformation. The objective of this investigation was to obtain information on the structures of metabolites excreted into rat urine and bile to understand the metabolic fate of bendamustine in vivo.