Pharmacokinetics and metabolism of galanthamine

Oral bioavailability of galanthamine was almost 100% in 8 healthy male Volunteers independent of formulation, with a lag time of 10-15 min and time of maximal plasma concentration of 45-52 min. First-pass effect could not be shown. Volume of distribution at steady state was 2.64 I/kg, total clearance was 340 ml/h/kg and renal clearance was 84 ml/h/kg. T-1/2 in plasma at steady state has been calculated at 5.6 h in young men. In the target population of Alzheimer patients, tin of 8 h and a total clearance of 250 ml/h/kg have been observed. Binding to plasma proteins appears negligible. Almost 50% of administered dose of galanthamine is eliminated via the urine, while similar to 25% is unmetabolized, 20% is metabolized as O-demethylgalanthamine-glucuronide, 5% as N-demethylgalanthamine and <2% as epigalanthamine or galanthaminone. O-Demethylation is catalyzed by cytochrome P4502D6 which underlies a genetic polymorphism in 5-10% of poor metabolizers among Caucasians. P4502D6 can be blocked 100% by quinidine in therapeutic doses which do not represent an added risk in terms of overdosing or toxicity of galanthamine. Tissue distribution has been studied in mice following nonionic diffusion, where galanthamine concentration in erythrocytes was 1.3, in brain 2.1, in liver 5.0, and in kidneys almost 10 times that in blood plasma. Simultaneous recordings of concentrations of galanthamine and activity of acetylcholinesterase in red blood cells and of the EEG have shown that the power density in the alpha 1 frequency band at the occipital region rose sharply at 40% enzyme inhibition. Data on intestinal elimination of galanthamine and epigalanthamine metabolites are not available.