Narcissus and Daffodil

336 D. Brown
Absorption
Galanthamine had almost complete (85–100%) oral bioavailability in man, when
formulated either as a solution or tablets (Mihailova et al., 1989; Bickel et al.,
1991b). In one study (Bickel et al., 1991b), the time to peak plasma concentration
(T max ) was shorter with a solution (15 minutes against 52 minutes). The half-life
of the absorption process was 20.4 minutes. In another study (Mihailova et al.,
1989), absorption from oral tablets was slower, with a T max in healthy volunteers
of approximately 120 minutes. The bioavailability data indicate that there is no
significant first-pass effect.
Therapeutically relevant drug concentrations, corresponding to 30–60% inhibition
of erythrocyte acetylcholinesterase (as recommended by Becker et al., 1991)
were reached within 30–44 minutes of administration.
Distribution
Data from studies in anaesthetised cats indicate that galanthamine has a large
volume of distribution but does not bind to plasma proteins significantly
(Mihailova et al., 1985). Single dose (0.3 mg/kg, IV) studies of galanthamine have
been carried out in eight female patients undergoing gynaecological surgery
(Westra et al., 1986). Galanthamine was given at the end of surgery to reverse
pancuronium-induced neuromuscular blockade. Serum levels were determined
by HPLC. Mean peak levels of 543± 47 ng/ml were observed at approximately
2 minutes. The serum level versus time curve showed biexponential decay after
the maximum was reached, indicating extensive distribution in a two-compartment
model. A mean distribution half-life (t 1/2 α) of 0.11 hours and an elimination halflife
(t 1/2 β) of 4.4 hours were calculated. The latter was considerably longer than
the half-lives of neostigmine (80 minutes) and pyridostigmine (46 minutes). The
volume of distribution at steady state was large (mean: 1.76 litre/kg, with a 95%
confidence interval (CI) of 1.22–2.30 litre/kg), indicating accumulation by various
tissues. The mean total serum clearance was 322.2 ml/h/kg and mean renal clearance
was 81.6 ml/h/kg.
Mihailova et al. (1989) administered single doses of 10 mg (0.11–0.18 mg/kg)
subcutaneously or orally, in an open crossover fashion, to eight male volunteers.
By these routes, the T max was prolonged (2 hours in each case) and peak serum
levels were 1.1–1.5 µg/ml and 1.0–1.4 µg/ml, respectively. The authors concluded
that the subcutaneous and oral formulations were essentially bioequivalent. These
values are higher than one might expect on the basis of the results of Westra et al.
(1986) who gave, on average, three times the dose of galanthamine intravenously.
The discrepancy is difficult to explain on the basis of different assay methods
employed in the two studies alone. Perhaps there are as yet unexplained differences
in age, sex or clinical status that determine the pharmacokinetics of galanthamine.
The t 1/2β values were 5.7 and 5.3 hours after oral and subcutaneous
doses, respectively.
Thomsen et al. (1990b) reported a pharmacokinetic study in one Alzheimer’s
patient and one volunteer. Repeated daily doses of 30–50 mg galanthamine
resulted in steady state plasma concentrations of 50–150 ng/ml. In the volunteer,
IV injections of 10 mg of the drug produced a peak plasma concentration of