The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6.
Galanthamine proved effective in symptomatic treatment of senile dementia of Alzheimer's type. The aim of this study was to elucidate the metabolism of galanthamine. Two novel metabolites of galanthamine have been isolated from the urine of eight young men after single doses of 10-15 mg. Some 19.8% of the doses were excreted as O-demethylgalanthamine glucuronide, 5% as N-demethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine. After coadministration of quinidine hydrogen sulfate, which inhibits cytochrome P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was highly diminished in urine. In vitro, human liver microsomes metabolized galanthamine to O-demethylgalanthamine with Vmax 5.2 nmol/mg protein/h and Km 187 microM. Ki of quinidine to inhibit O-demethylation was 28 nM. To inhibit cholinesterases, O-demethylgalanthamine was 10-fold more selective for acetylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanthamine. After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE. N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine.
Bachus
R
R
Department of Psychiatry, University Clinic Charité, Humboldt University, Berlin, Germany.
Bickel
U
U
Thomsen
T
T
Roots
I
I
Kewitz
H
H
D000110:Acetylcholinesterase / Q000187:drug effects; D000328:Adult; D002091:Butyrylcholinesterase / Q000187:drug effects; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics* / Q000652:urine; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005702:Galantamine / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D008862:Microsomes, Liver / Q000201:enzymology; D018697:Nootropic Agents / Q000493:pharmacokinetics* / Q000652:urine; D012016:Reference Values
D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D005702:Galantamine; D019389:Cytochrome P-450 CYP2D6; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase