The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6

Galanthamine proved effective in symptomatic treatment of senile dementia o f Alzheimer's type. The aim of this study was to elucidate the metabolism o f galanthamine, True novel metabolites of galanthamine have been isolated f rom the mine 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-d emethylgalanthamine, 25.1% as galanthamine, and 0.8% as epigalanthamine, Af ter coadministration of quinidine hydrogen sulfate, which inhibits cytochro me P450 2D6 (CYP2D6) selectively, O-demethylgalanthamine glucuronide was hi ghly diminished in urine. In vitro, human liver microsomes metabolized gala nthamine to O-demethylgalanthamine with V-max 5.2 nmol/mg protein/h and K-m 187 mu M. K-i of quinidine to inhibit O-demethylation was 28 nM. To inhibi t cholinesterases, O-demethylgalanthamine was 10-fold more selective for ac etylcholinesterase (AChE) versus butyrylcholinesterase (BuChE) than galanth amine, After glucuronidation, O-demethylgalanthamine failed to inhibit AChE and BuChE, N-Demethylgalanthamine inhibited cholinesterases less potently than galanthamine. Pharmacogenetics 9:661-668 (C) 1999 Lippincott Williams & Wilkins.