Phase I metabolism of ganstigmine. Rat, dog, monkey and human liver microsomal extracts investigated by liquid chromatography electrospray tandem mass spectrometry.
Ganstigmine, a new acetylcholinesterase inhibitor, was incubated with rat liver microsomes and the resulting metabolites were identified by high-performance liquid chromatographic/mass spectrometric (HPLC/MS) and HPLC/MS/MS analyses. The results showed the formation of eight main metabolites, among which geneseroline and molecules corresponding to mono-hydroxylated, demethylated and reduced ganstigmine. The metabolic profile drawn for humans, dog and monkey showed a pattern very similar to that of rat: only in the case of liver dog microsomes higher amounts of geneseroline and of a metabolite identified as demethylated and reduced drug were detected.
Catinella
S
S
Chiesi Farmaceutici SpA, R&D, Analytical Chemistry and Pharmacokinetics Departments, Via Palermo 26/A, I-43100 Parma, Italy. s.catinella@chiesigroup.com
Pelizzi
N
N
Puccini
P
P
Marchetti
S
S
Zanol
M
M
Acerbi
D
D
Ventura
P
P
D000470:Alkaloids / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002219:Carbamates / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D006801:Humans; D006900:Hydroxylation; D008252:Macaca fascicularis; D008297:Male; D013058:Mass Spectrometry; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity
D000470:Alkaloids; D002219:Carbamates; D002800:Cholinesterase Inhibitors; C447079:ganstigmine