Narcissus and Daffodil

Pharmacology of Narcissus compounds 337
182 ng/ml. The half-life was reported to be 8–10 hours. These values are closer to
those reported by Westra et al. (1986). In a further study in eight male volunteers,
Bickel et al. (1991b) observed a maximum plasma concentration of 30–60 ng/ml
after oral administration of 10 mg galanthamine and 50–100 ng/ml after the same
dose given by constant rate IV infusion over 30 minutes. Galanthamine showed
linear, first order pharmacokinetics. The mean values for t1/2α and t1/2β were 0.16
hours and 5.68 hours, respectively. The mean total clearance was 340 ml/h/kg and
renal clearance was 84 ml/h/kg. A steady state volume of distribution of 2.64 litre/kg
(95% CI: 2.41–2.90 litre/kg) was calculated. Twenty-five percent of the dose was
excreted unchanged in the urine. Little evidence of metabolism was found: negligible
amounts of epigalanthamine and galanthaminone were detected in blood
and urine.
Most recently, Kewitz (1997) reported data from a 15-week clinical trial of
galanthamine in 34 patients with Alzheimer’s disease, whose mean age was 75
years. A mean volume of distribution of 2.9 litre/kg, a half-life of 8.1 hours and a
plasma clearance of 250 ml/h/kg were calculated. As might be expected and
certainly should be remembered, clearance was 30% less in this elderly population
than in healthy young volunteers.
There is no direct in vivo evidence that galanthamine itself enters the human
brain. However, examination of its structure (see Figure 13.1) reveals a tertiary
nitrogen atom in common with many molecules that can penetrate the bloodbrain
barrier. Indirectly, there is biochemical evidence from experiments in rats
(Mihailova and Yomboliev, 1986). One and 3 mg/kg intravenous doses produced
peak levels of 5 and 6.3 µg/g of brain tissue, respectively, 10–15 minutes after
injection, declining to about 10% between 1 and 3 hours. In mice, parenteral
administration of galanthamine resulted in accumulation in brain, liver and
kidney tissue (Bickel et al., 1991a).
Correlation of galanthamine pharmacokinetics with erythrocyte
cholinesterase inhibition
The inhibition of acetylcholinesterase in human erythrocytes correlates closely
with the pharmacokinetics of galanthamine. A median maximal value of 53%
inhibition was reported after a single, intravenous dose of 10 mg (Bickel et al.,
1991b). The in vitro and ex vivo concentration responses were essentially identical,
indicating that galanthamine alone, and not its metabolites, was responsible for
inhibition of cholinesterase. In a previous study (Thomsen et al., 1990a), erythrocyte
acetylcholinesterase activity returned to normal some 30 hours after both
single dose and chronic administration at therapeutic doses (10–40 mg daily), illustrating
the reversible nature of the inhibition of the enzyme by galanthamine.
Kewitz (1997) recently presented data to show the relationship between the
serum level of galanthamine, enzyme inhibition in erythrocytes and central
nervous system (CNS) effects. Simultaneous EEG recordings were made in a
healthy young male volunteer, during an IV infusion of 15 mg galanthamine. The
power density of the alpha-one frequency band of the EEG at the occipital region
began 7 minutes after starting the infusion, when 40% of the enzyme activity had
been blocked. Power density fluctuated in synchrony with enzyme activity as the
galanthamine levels fell after the infusion was stopped.