Characterization of Ganstigmine metabolites in hepatocytes by low- and high-resolution mass spectrometry coupled with liquid chromatography.
In order to deepen the understanding of the metabolism of Ganstigmine, a new acetylcholinesterase inhibitor under evaluation for the treatment of Alzheimer's disease, samples obtained by incubating the drug with female rat hepatocytes were investigated by low-resolution liquid chromatography/tandem mass spectrometry (LC/MS/MS). The results confirmed the formation of most of the phase I metabolites already demonstrated, but also three new species. The combination of high-resolution quadrupole time-of-flight (Q-TOF) LC/MS and LC/MS/MS measurements, and the evaluation of the more reasonable metabolic routes, allowed the identification of the new metabolites as Geneseroline-glucuronide and oxidized and rearranged Ganstigmine. Analogous investigations were made using hepatocytes from male rat and dog, and both gender monkeys and humans, to compare the metabolic patterns. The results did not indicate substantial differences in terms of numbers and abundances of detected metabolites among the considered species, and also between male and female hepatocytes within each species.
Pelizzi
Nicola
N
Chiesi Farmaceutici S.p.A, R & D, Analytical Chemistry and Pharmacokinetics Departments, Via Palermo 26/A, 43100 Parma, Italy.
Puccini
Paola
P
Riccardi
Benedetta
B
Acerbi
Daniela
D
Catinella
Silvia
S
D000470:Alkaloids / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002219:Carbamates / Q000032:analysis / Q000378:metabolism / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid / Q000295:instrumentation / Q000379:methods*; D004285:Dogs; D020719:Glucuronides / Q000032:analysis / Q000378:metabolism; D000882:Haplorhini; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D013058:Mass Spectrometry / Q000295:instrumentation / Q000379:methods*; D051381:Rats; D013045:Species Specificity
D000470:Alkaloids; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D020719:Glucuronides; C060404:geneseroline; C447079:ganstigmine