Pharmacokinetics and Tissue Distribution of Galantamine and Galantamine-related Radioactivity after Single Intravenous and Oral Administration in the Rat

Abstract

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.

Distribution of Intravenously Administered Acetylcholinesterase Inhibitor and Acetylcholinesterase Activity in the Adrenal Gland: 11C-Donepezil PET Study in the Normal Rat

“…This rapid increase and washout pattern in the kidney was usually observed in many PET studies, and not reflecting the specific binding to AChE. A previous study evaluated the pharmacokinetics and tissue distribution after oral administration of 3 H-galantamine, an AChE inhibitory drug recently developed for Alzheimer's disease, and reported the following ratios of the 0–24 h area under the curve of tissue to plasma; liver (10.6), kidney (7.47), salivary gland (4.45), adrenal gland (3.32), spleen (2.92), and brain (0.60) [9]. These results were consistent with our results, although the tracer and administration method were different.…”

Galantamine, an acetylcholinesterase inhibitor, reduces brain damage induced by hypoxia‐ischemia in newborn rats

“…In this experiment, we injected galantamine (5 mg/kg, n = 14; 2.5 mg/kg, n = 9; 1.0 mg/kg, n = 11) intraperitoneally just before 2 h of hypoxia to examine the attenuating effect on brain damage with decreasing accumulation of microglia. These doses were determined in reference to previous experimental doses for adult rats (van Beijsterveldt et al, 2004). Another group of pups received an equivalent volume of saline ( n = 31) to compare the degree of hypoxic‐ischemic brain damage and the accumulation of microglia in different brain regions including the hippocampus and cortex.…”

Positive allosteric modulation of α4β2 nicotinic acetylcholine receptors as a new approach to smoking reduction: evidence from a rat model of nicotine self-administration

“…In a separate groups of rats, the effects of the α4β2 nAChR-selective agonist 5-iodo-A-85380 (Mukhin et al 2000) and galantamine, a PAM at α7 nAChRs and acetylcholinesterase inhibitor (Maelicke et al 2000; Schrattenholz et al 1996), were also examined. Because the half-life of these compounds ranged from 1.9 to 8.6 hours (Goh et al 2011; Ueda et al 2004; van Beijsterveldt et al 2004; present study), the drug test sessions were scheduled on every other day in order to eliminate any carry-over effect of these compounds and for lever responses to return to baseline level prior to each test session.…”