Narcissus and Daffodil

Pharmacology of Narcissus compounds 339
on the excretion of galanthamine or its metabolites in bile or the intestinal tract.
The notion that galanthamine is not extensively metabolised is also supported by
animal data (Harvey, 1995).
More recently, Bachus (1995) showed that in male volunteers, 20% of a dose of
galanthamine appeared in urine as O-demethylgalanthamine glucuronide, 5% as
N-demethylgalanthamine and < 2% as epigalanthamine resulting from the intermediate
metabolite galanthaminone, which itself was present in traces only.
O-demethylgalanthamine is 3–10 times more active than galanthamine, but rapid
glucuronidation reduces this by a factor of at least one hundred. All the other
galanthamine metabolites identified thus far have little anticholinesterase activity.
O-demethylation is catalysed by the cytochrome isoenzyme CYP2D6. This knowledge
should allow the avoidance of concomitant drugs that are also metabolised
predominantly by this isoenzyme (such as beta-blockers, haloperidol, morphine,
phenothiazines and some tricyclic and selective serotonin reuptake inhibitor
antidepressants) and thus decrease the potential for drug interactions through
metabolism induction or inhibition. Fluoxetine, haloperidol, morphine and quinidine
are known to inhibit CYP2D6, but the problem may be largely theoretical.
Co-adminstration of therapeutic doses of quinidine, a potent inhibitor of CYP2D6,
to four healthy volunteers completely suppressed O-demethylation but led to only
a modest (20%) rise in galanthamine serum levels. Kewitz (1997) claimed that this
rise was unlikely to cause toxicity and concluded that co-administration of other
drugs inhibiting the same enzyme would do little damage. Neither would problems
be likely in poor metabolisers, deficient in CYP2D6 (5–10% of Caucasians and 1%
of Asians), however caution is advisable. No comment was made on the likely outcome
if other interacting drugs were used in poor metabolisers or in those with
kidney dysfunction. Potential inhibitors of the isoenzyme CYP3A4 should also be
viewed with caution, as this enzyme also plays a part in galanthamine metabolism.
Comparison with other relevant drugs
Galanthamine pharmacokinetics appear to be more attractive than those of some,
but not all, other anticholinesterases currently under investigation for the treatment
of Alzheimer’s disease. Physostigmine has poor oral bioavailability (approx. 10%)
and a short half life (