Metabolic Fate of Eptastigmine, a New Competitive Inhibitor of Acetylcholinesterase. (I). Absorption, Distribution and Excretion of 3H-Eptastigmine after Single Oral Administration in Rats.

Abstract

Eptastigmine, ((3aS, 8aR)-1, 2, 3, 3a, 8, 8a-hexahydro-1, 3a, 8-trimethylpyrrolo [2, 3-b] indol-5-ol-heptylcarbamate L-tartrate), is a competitive inhibitor of acetylcholinesterase. Absorption, distribution and excretion of radioactivity were investigated in rats (n=3) after single oral or intravenous administration of 3H-eptastigmine. 1. After oral administration of doses ranging from 2 to 8mg/kg, blood levels of radioactivity increased proportionally to administered dose with peak blood concentration occurring at about one hour and declined with half-lives (t1/2β) of 13-16hr. Based on the AUC values obtained after intravenous and oral administration, oral absorption ratio of 3H-eptastigmine was estimated to be 70-100%. 2. After oral dosin g, the radioactivity was rapidly and widely distributed to tissues and maintained in high concentrations in the liver and gastrointestinal tract. Radioactivity in most of tissues declined slower than that in the plasma. At 24hr, the level in each tissue decreased to about 10% of the corresponding maximum level. There was no evidence of accumulation of 3H in any tissue. 3. Mean excretion of radioactivity was 60.5 and 18.1% of the dose in the urine and feces, respectively, within 24hr after intravenous dosing. In case of oral dosing, the mean excretion of radioactivity in urine and feces were 40.2-51.3 and 29.0-33.5% of the dose, respectively. 4. Mean plasma levels of unchanged eptastigmine reached the maximum concentration at 0.5hr after oral dosing, and then declined with half-life of 1.1hr. The AUC value for unchanged eptastigmine accounted only for 0.4% of that for the total radioactivity. 5. Marked inhibition of RBC acetylcholinesterase activity was o bserved after administration of the 8mg/kg. At 1hr after dosing, the mean value of acetylcholinesterase activity decreased to 15% of the pre-dosing level and remained suppressed for up to 8hr after dosing. 6. Based on the results from the blood profile of radioactivity and time course of acetylcholinesterase inhibition, we concluded that at least one active metabolite exists in the blood.