Galanthamine: pharmacokinetics, tissue distribution and cholinesterase inhibition in brain of mice

Abstract Galanthamine was determined in plasma and tissue extracts of mice, after the application of 4, 6 and 8 mg/kg (i.V.), by reverse phase HPLC, with fluorescence detection. A biexponential decline of concentrations in plasma, with a terminal half-life of 43.3 min, was observed after the dose of 4 mg/kg. The volume of distribution ( V ss ) of 2.17 l/kg was similar to that found in other species, including man. Metabolism to the inactive diastereomer, epigalanthamine, was very limited. There was a rapid accumulation of galanthamine in tissues, which was most pronounced in the kidney (10-fold compared to plasma) and liver (5-fold). In brain, accumulation was similar to other parenchymatous organs (diaphragm, lung) and amounted to 2.10-fold. Red blood cells showed a concentration 1.34-fold greater than plasma. The accumulation of galanthamine in tissue, with the exception of liver and kidney, can be explained by passive distribution according to differences in pH, between intra- and extracellular compartments. Extraction of galanthamine from blood to brain tissue was complete, indicated by a clearance in the range of cerebral blood flow (1.05ml min − g −1 ). The concentration-time course of galanthamine in brain tissue was parallel to that in plasma during the terminal elimination phase. Measurement of inhibition of acetylcholinesterase (AChE) in the same samples from brain revealed a maximum apparent inhibition of 43% in the homogenate of brain (1:4 w v in phosphate buffer, 4 mg/kg, 5 min after injection). Measured inhibition of AChE and estimated values, taken from the in vitro concentration-response curve (IC 50 3.9 × 10 −6 M) and from measured concentrations of galanthamine, displayed a good concordance over the period examined (1–180 min after application). The feasibility of estimating inhibition of AChE in vivo from measured concentrations in plasma and in vitro concentration-inhibition curves is discussed.