Preferential cerebrospinal fluid acetylcholinesterase inhibition by rivastigmine in humans

This study sought to examine the feasibility of prolonged assessment of ace tylcholinesterase (AChE) activity in the cerebrospinal fluid (CSF) of volun teers and to test the hypothesis that rivastigmine (ENA-713; Exelon(R), Nov artis Pharma AG, Basel, Switzerland) selectively inhibits AChE in CSF in hu mans at a dose producing minimal inhibition of the peripheral enzyme, Lumba r CSF samples were collected continuously (0.1 mL . min(-1)) for 49 hours f rom eight healthy volunteers who took either placebo or a single oral dose of rivastigmine (3 mg), CSF specimens and samples of blood cells and blood plasma were analyzed at intervals for rivastigmine and its metabolite NAP 2 26-90 ([-] [3-([1-dimethylamino]ethyl)-phenol]), erythrocyte AChE activity, CSF AChE activity, and plasma and CSF butyrylcholinesterase (BuChE) activi ty. Safety evaluations were performed 23 hours after drug dosing and at the end of the study. Evaluable data were obtained from six subjects. The mean time to maximal rivastigmine plasma concentration (t(max)) was 0.83 +/- 0. 26 hours, the mean maximal plasma concentration (C-max) was 4.88 +/- 3.82 n g . mL(-1), the mean plasma area under the concentration versus time curve (AUC(0-infinity)) was 7.43 +/- 4.74 ng . hr . mL(-1), and the mean plasma t (1/2) was 0.85 +/- 0.115 hours. The concentration of rivastigmine in CSF wa s lower than the quantification Limit for assay (0.65 ng . mL(-1)), but NAP 226-90 reached a mean C-max of 3.14 +/- 0.57 ng . mL(-1). Only minimal inh ibition of erythrocyte AChE activity (approximately 3%) was observed, Inhib ition of AChE in the CSF after rivastigmine administration was significantl y greater than after placebo for up to 8.4 hours after the dose and was max imal (40%) at 2.4 hours. Plasma BuChE activity was significantly lower afte r rivastigmine than after placebo, but this was not clinically relevant, Bu ChE activity in CSF was significantly lower after rivastigmine than after p lacebo for up to 3.6 hours after dosing, but this difference was not sustai ned. This study confirms the feasibility of using continuous measurement of AChE activity in CSF over prolonged periods, that rivastigmine markedly in hibits CSF AChE after a single oral dose of 3 mg, and that the inhibition o f central AChE is substantially greater than that of peripheral AChE or BuC hE.