Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat.

The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible acetylcholinesterase inhibitor, were studied in male and female non-pregnant and pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most studies were performed using 3H-labelled galantamine hydrobromide, measuring unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by high-performance liquid chromatography (HPLC), liquid scintillation counting and quantitative whole-body autoradiography (QWBA). Plasma levels after single intravenous administration of UD (1.25-2.5 mg/kg) declined bi- or triphasically, with an elimination half-life of 3.5 h in male, and 5.1 h in female rats. The plasma clearance (Cl) averaged 1.9 l/kg/h (male rats) and 0.9 l/kg/h (female rats), and the volume of distribution (VdSS) was about 5 l/kg for both male and female rats. Following oral administration (2.5-10 mg/kg), galantamine was rapidly absorbed in both sexes, with an absolute oral bioavailability of 77%. Distribution studies after oral administration of 3H-galantamine showed an almost immediate equilibrium between plasma and tissues, with highest tissue levels of NVR and UD in liver, kidney, salivary glands, adrenal glands and, for the female rat, spleen, and lowest in white fat. To most tissues and especially to brain, the distribution of UD was more pronounced than that of its metabolites. Tissue concentrations of UD and NVR declined at a similar rate as plasma, showing no undue retention. QWBA in the pigmented rat showed the same distribution and elimination pattern of NVR. Only in hair follicles and choroid some retention of NVR was seen, but the calculated half-life was less than one day. In the female pregnant SPF Wistar rat, maternal tissue distribution of NVR was similar to that of the non-pregnant rat. NVR tissue levels in the foetus were similar to those found in maternal blood during the whole experiment, indicating a rapid equilibrium without accumulation.